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He E, Ma R, Qu S, Zheng X, Peng X, Ji J, Ma W, Zhang X, Li Y, Li H, Li Y, Li L, Gong Z. L-methionine and the L-type Ca 2+ channel agonist BAY K 8644 collaboratively contribute to the reduction of depressive-like behavior in mice. Front Neural Circuits 2024; 18:1435507. [PMID: 39268349 PMCID: PMC11391425 DOI: 10.3389/fncir.2024.1435507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 08/07/2024] [Indexed: 09/15/2024] Open
Abstract
The L-type Ca2+ channel (LTCC, also known as Cav1,2) is involved in the regulation of key neuronal functions, such as dendritic information integration, cell survival, and neuronal gene expression. Clinical studies have shown an association between L-type calcium channels and the onset of depression, although the precise mechanisms remain unclear. The development of depression results from a combination of environmental and genetic factors. DNA methylation, a significant epigenetic modification, plays a regulatory role in the pathogenesis of psychiatric disorders such as posttraumatic stress disorder (PTSD), depression, and autism. In our study, we observed reduced Dnmt3a expression levels in the hippocampal DG region of mice with LPS-induced depression compared to control mice. The antidepressant Venlafaxine was able to increase Dnmt3a expression levels. Conversely, Bay K 8644, an agonist of the L-type Ca2+ channel, partially ameliorated depression-like behaviors but did not elevate Dnmt3a expression levels. Furthermore, when we manipulated DNA methylation levels during Bay K 8644 intervention in depression-like models, we found that enhancing the expression of Dnmt3a could improve LPS-induced depression/anxiety-like behaviors, while inhibiting DNA methylation exacerbated anxiety-like behaviors, the combined use of BAY K 8644 and L-methionine can better improve depressive-like behavior. These findings indicate that DNA methylation plays a role in the regulation of depression-like behaviors by the L-type Ca2+ channel, and further research is needed to elucidate the interactions between DNA methylation and L-type Ca2+ channels.
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Affiliation(s)
- Ershu He
- School of Medicine, Dali University, Dali, China
| | - Ruixue Ma
- School of Medicine, Dali University, Dali, China
| | - Shanglan Qu
- School of Medicine, Dali University, Dali, China
- Faculty of Health and Medical Sciences, School of Pharmacy, Taylor's University, Subang Jaya, Malaysia
| | - Xiaoye Zheng
- School of Medicine, Dali University, Dali, China
| | - Xin Peng
- School of Medicine, Dali University, Dali, China
| | - Jieyu Ji
- School of Medicine, Dali University, Dali, China
| | - Wenhao Ma
- School of Medicine, Dali University, Dali, China
| | - Xueyan Zhang
- School of Medicine, Dali University, Dali, China
| | - Ying Li
- School of Medicine, Dali University, Dali, China
| | - Hanwei Li
- School of Medicine, Dali University, Dali, China
| | - Yanjiao Li
- School of Medicine, Dali University, Dali, China
| | - Lijuan Li
- School of Medicine, Dali University, Dali, China
| | - Zhiting Gong
- School of Medicine, Dali University, Dali, China
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Le Belle JE, Condro M, Cepeda C, Oikonomou KD, Tessema K, Dudley L, Schoenfield J, Kawaguchi R, Geschwind D, Silva AJ, Zhang Z, Shokat K, Harris NG, Kornblum HI. Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.08.602602. [PMID: 39026891 PMCID: PMC11257517 DOI: 10.1101/2024.07.08.602602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and neuro-inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that might be expected to alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction and related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, and repetitive behaviors and sensory over-responsivity in adult offspring with persistent brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-,ion channel-, and epilepsy-associated genes, in the same time frame. Our findings suggest that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction, including neuronal excitability, altered gene expression in multiple cell types, sensory functional network connectivity, and modulation of information flow. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD behaviors in adult animals without requiring long-term physical alterations to the brain. Thus, restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing both primary sensory and social behavior phenotypes, and compensatory repetitive behavior phenotypes.
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Courtney Y, Head JP, Yimer ED, Dani N, Shipley FB, Libermann TA, Lehtinen MK. A choroid plexus apocrine secretion mechanism shapes CSF proteome and embryonic brain development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.08.574486. [PMID: 38260341 PMCID: PMC10802501 DOI: 10.1101/2024.01.08.574486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
We discovered that apocrine secretion by embryonic choroid plexus (ChP) epithelial cells contributes to the cerebrospinal fluid (CSF) proteome and influences brain development in mice. The apocrine response relies on sustained intracellular calcium signaling and calpain-mediated cytoskeletal remodeling. It rapidly alters the embryonic CSF proteome, activating neural progenitors lining the brain's ventricles. Supraphysiological apocrine secretion induced during mouse development by maternal administration of a serotonergic 5HT2C receptor agonist dysregulates offspring cerebral cortical development, alters the fate of CSF-contacting neural progenitors, and ultimately changes adult social behaviors. Critically, exposure to maternal illness or to the psychedelic drug LSD during pregnancy also overactivates the ChP, inducing excessive secretion. Collectively, our findings demonstrate a new mechanism by which maternal exposure to diverse stressors disrupts in utero brain development.
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Shih YC, Nelson L, Janeček M, Peixoto RT. Late onset and regional heterogeneity of synaptic deficits in cortical PV interneurons of Shank3B -/- mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.23.568500. [PMID: 38045377 PMCID: PMC10690261 DOI: 10.1101/2023.11.23.568500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Epilepsy and epileptiform patterns of cortical activity are highly prevalent in autism spectrum disorders (ASDs), but the neural substrates and pathophysiological mechanisms underlying the onset of cortical dysfunction in ASD remains elusive. Reduced cortical expression of Parvalbumin (PV) has been widely observed in ASD mouse models and human postmortem studies, suggesting a crucial role of PV interneurons (PVINs) in ASD pathogenesis. Shank3B -/- mice carrying a Δ13-16 deletion in SHANK3 exhibit cortical hyperactivity during postnatal development and reduced sensory responses in cortical GABAergic interneurons in adulthood. However, whether these phenotypes are associated with PVIN dysfunction is unknown. Using whole-cell electrophysiology and a viral-based strategy to label PVINs during postnatal development, we performed a developmental characterization of AMPAR miniature excitatory postsynaptic currents (mEPSCs) in PVINs and pyramidal (PYR) neurons of layer (L) 2/3 mPFC in Shank3B -/- mice. Surprisingly, reduced mEPSC frequency was observed in both PYR and PVIN populations, but only in adulthood. At P15, when cortical hyperactivity is already observed, both neuron types exhibited normal mEPSC amplitude and frequency, suggesting that glutamatergic connectivity deficits in these neurons emerge as compensatory mechanisms. Additionally, we found normal mEPSCs in adult PVINs of L2/3 somatosensory cortex, revealing region-specific phenotypic differences of cortical PVINs in Shank3B -/- mice. Together, these results demonstrate that loss of Shank3 alters PVIN function but suggest that PVIN glutamatergic synapses are a suboptimal therapeutic target for normalizing early cortical imbalances in SHANK3-associated disorders. More broadly, these findings underscore the complexity of interneuron dysfunction in ASDs, prompting further exploration of region and developmental stage specific phenotypes for understanding and developing effective interventions.
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Ren D, Luo B, Chen P, Yu L, Xiong M, Fu Z, Zhou T, Chen WB, Fei E. DiGeorge syndrome critical region gene 2 (DGCR2), a schizophrenia risk gene, regulates dendritic spine development through cell adhesion. Cell Biosci 2023; 13:134. [PMID: 37480133 PMCID: PMC10362570 DOI: 10.1186/s13578-023-01081-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 07/06/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND Dendritic spines are the sites of excitatory synapses on pyramidal neurons, and their development is crucial for neural circuits and brain functions. The spine shape, size, or number alterations are associated with neurological disorders, including schizophrenia. DiGeorge syndrome critical region gene 2 (DGCR2) is one of the deleted genes within the 22q11.2 deletion syndrome (22q11DS), which is a high risk for developing schizophrenia. DGCR2 expression was reduced in schizophrenics. However, the pathophysiological mechanism of DGCR2 in schizophrenia or 22q11DS is still unclear. RESULTS Here, we report that DGCR2 expression was increased during the neurodevelopmental period and enriched in the postsynaptic densities (PSDs). DGCR2-deficient hippocampal neurons formed fewer spines. In agreement, glutamatergic transmission and synaptic plasticity were decreased in the hippocampus of DGCR2-deficient mice. Further molecular studies showed that the extracellular domain (ECD) of DGCR2 is responsible for its transcellular interaction with cell adhesion molecule Neurexin1 (NRXN1) and spine development. Consequently, abnormal behaviors, like anxiety, were observed in DGCR2-deficient mice. CONCLUSIONS These observations indicate that DGCR2 is a novel cell adhesion molecule required for spine development and synaptic plasticity, and its deficiency induces abnormal behaviors in mice. This study provides a potential pathophysiological mechanism of DGCR2 in 22q11DS and related mental disorders.
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Affiliation(s)
- Dongyan Ren
- School of Life Sciences, Nanchang University, Nanchang, 330031, China
- Institute of Life Science, Nanchang University, Nanchang, 330031, China
| | - Bin Luo
- Institute of Life Science, Nanchang University, Nanchang, 330031, China
| | - Peng Chen
- Institute of Life Science, Nanchang University, Nanchang, 330031, China
| | - Lulu Yu
- Institute of Life Science, Nanchang University, Nanchang, 330031, China
| | - Mingtao Xiong
- Institute of Life Science, Nanchang University, Nanchang, 330031, China
| | - Zhiqiang Fu
- Institute of Life Science, Nanchang University, Nanchang, 330031, China
| | - Tian Zhou
- School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China
| | - Wen-Bing Chen
- Institute of Life Science, Nanchang University, Nanchang, 330031, China.
| | - Erkang Fei
- School of Life Sciences, Nanchang University, Nanchang, 330031, China.
- Institute of Life Science, Nanchang University, Nanchang, 330031, China.
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6
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Molloy CJ, Cooke J, Gatford NJF, Rivera-Olvera A, Avazzadeh S, Homberg JR, Grandjean J, Fernandes C, Shen S, Loth E, Srivastava DP, Gallagher L. Bridging the translational gap: what can synaptopathies tell us about autism? Front Mol Neurosci 2023; 16:1191323. [PMID: 37441676 PMCID: PMC10333541 DOI: 10.3389/fnmol.2023.1191323] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/24/2023] [Indexed: 07/15/2023] Open
Abstract
Multiple molecular pathways and cellular processes have been implicated in the neurobiology of autism and other neurodevelopmental conditions. There is a current focus on synaptic gene conditions, or synaptopathies, which refer to clinical conditions associated with rare genetic variants disrupting genes involved in synaptic biology. Synaptopathies are commonly associated with autism and developmental delay and may be associated with a range of other neuropsychiatric outcomes. Altered synaptic biology is suggested by both preclinical and clinical studies in autism based on evidence of differences in early brain structural development and altered glutamatergic and GABAergic neurotransmission potentially perturbing excitatory and inhibitory balance. This review focusses on the NRXN-NLGN-SHANK pathway, which is implicated in the synaptic assembly, trans-synaptic signalling, and synaptic functioning. We provide an overview of the insights from preclinical molecular studies of the pathway. Concentrating on NRXN1 deletion and SHANK3 mutations, we discuss emerging understanding of cellular processes and electrophysiology from induced pluripotent stem cells (iPSC) models derived from individuals with synaptopathies, neuroimaging and behavioural findings in animal models of Nrxn1 and Shank3 synaptic gene conditions, and key findings regarding autism features, brain and behavioural phenotypes from human clinical studies of synaptopathies. The identification of molecular-based biomarkers from preclinical models aims to advance the development of targeted therapeutic treatments. However, it remains challenging to translate preclinical animal models and iPSC studies to interpret human brain development and autism features. We discuss the existing challenges in preclinical and clinical synaptopathy research, and potential solutions to align methodologies across preclinical and clinical research. Bridging the translational gap between preclinical and clinical studies will be necessary to understand biological mechanisms, to identify targeted therapies, and ultimately to progress towards personalised approaches for complex neurodevelopmental conditions such as autism.
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Affiliation(s)
- Ciara J. Molloy
- Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Jennifer Cooke
- Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Nicholas J. F. Gatford
- Kavli Institute for Nanoscience Discovery, Nuffield Department of Clinical Neurosciences, University of Oxford, Medical Sciences Division, Oxford, United Kingdom
| | - Alejandro Rivera-Olvera
- Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Sahar Avazzadeh
- Physiology and Cellular Physiology Research Laboratory, CÚRAM SFI Centre for Research in Medical Devices, School of Medicine, Human Biology Building, University of Galway, Galway, Ireland
| | - Judith R. Homberg
- Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Joanes Grandjean
- Physiology and Cellular Physiology Research Laboratory, CÚRAM SFI Centre for Research in Medical Devices, School of Medicine, Human Biology Building, University of Galway, Galway, Ireland
- Department of Medical Imaging, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Cathy Fernandes
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Sanbing Shen
- Regenerative Medicine Institute, School of Medicine, University of Galway, Galway, Ireland
- FutureNeuro, The SFI Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons, Dublin, Ireland
| | - Eva Loth
- Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Deepak P. Srivastava
- MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Louise Gallagher
- Department of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland
- The Hospital for SickKids, Toronto, ON, Canada
- The Peter Gilgan Centre for Research and Learning, SickKids Research Institute, Toronto, ON, Canada
- The Centre for Addiction and Mental Health, Toronto, ON, Canada
- Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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7
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Carbonell AU, Freire-Cobo C, Deyneko IV, Dobariya S, Erdjument-Bromage H, Clipperton-Allen AE, Page DT, Neubert TA, Jordan BA. Comparing synaptic proteomes across five mouse models for autism reveals converging molecular similarities including deficits in oxidative phosphorylation and Rho GTPase signaling. Front Aging Neurosci 2023; 15:1152562. [PMID: 37255534 PMCID: PMC10225639 DOI: 10.3389/fnagi.2023.1152562] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 04/17/2023] [Indexed: 06/01/2023] Open
Abstract
Specific and effective treatments for autism spectrum disorder (ASD) are lacking due to a poor understanding of disease mechanisms. Here we test the idea that similarities between diverse ASD mouse models are caused by deficits in common molecular pathways at neuronal synapses. To do this, we leverage the availability of multiple genetic models of ASD that exhibit shared synaptic and behavioral deficits and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare their hippocampal synaptic proteomes. Comparative analyses of mouse models for Fragile X syndrome (Fmr1 knockout), cortical dysplasia focal epilepsy syndrome (Cntnap2 knockout), PTEN hamartoma tumor syndrome (Pten haploinsufficiency), ANKS1B syndrome (Anks1b haploinsufficiency), and idiopathic autism (BTBR+) revealed several common altered cellular and molecular pathways at the synapse, including changes in oxidative phosphorylation, and Rho family small GTPase signaling. Functional validation of one of these aberrant pathways, Rac1 signaling, confirms that the ANKS1B model displays altered Rac1 activity counter to that observed in other models, as predicted by the bioinformatic analyses. Overall similarity analyses reveal clusters of synaptic profiles, which may form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Our results suggest that ASD-linked susceptibility genes ultimately converge on common signaling pathways regulating synaptic function and propose that these points of convergence are key to understanding the pathogenesis of this disorder.
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Affiliation(s)
- Abigail U. Carbonell
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Carmen Freire-Cobo
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Ilana V. Deyneko
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Saunil Dobariya
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Hediye Erdjument-Bromage
- Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, United States
| | - Amy E. Clipperton-Allen
- Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL, United States
| | - Damon T. Page
- Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL, United States
| | - Thomas A. Neubert
- Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, United States
| | - Bryen A. Jordan
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
- Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States
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8
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Medina E, Peterson S, Ford K, Singletary K, Peixoto L. Critical periods and Autism Spectrum Disorders, a role for sleep. Neurobiol Sleep Circadian Rhythms 2023; 14:100088. [PMID: 36632570 PMCID: PMC9826922 DOI: 10.1016/j.nbscr.2022.100088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Brain development relies on both experience and genetically defined programs. Time windows where certain brain circuits are particularly receptive to external stimuli, resulting in heightened plasticity, are referred to as "critical periods". Sleep is thought to be essential for normal brain development. Importantly, studies have shown that sleep enhances critical period plasticity and promotes experience-dependent synaptic pruning in the developing mammalian brain. Therefore, normal plasticity during critical periods depends on sleep. Problems falling and staying asleep occur at a higher rate in Autism Spectrum Disorder (ASD) relative to typical development. In this review, we explore the potential link between sleep, critical period plasticity, and ASD. First, we review the importance of critical period plasticity in typical development and the role of sleep in this process. Next, we summarize the evidence linking ASD with deficits in synaptic plasticity in rodent models of high-confidence ASD gene candidates. We then show that the high-confidence rodent models of ASD that show sleep deficits also display plasticity deficits. Given how important sleep is for critical period plasticity, it is essential to understand the connections between synaptic plasticity, sleep, and brain development in ASD. However, studies investigating sleep or plasticity during critical periods in ASD mouse models are lacking. Therefore, we highlight an urgent need to consider developmental trajectory in studies of sleep and plasticity in neurodevelopmental disorders.
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Affiliation(s)
- Elizabeth Medina
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Sarah Peterson
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Kaitlyn Ford
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Kristan Singletary
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
| | - Lucia Peixoto
- Department of Translational Medicine and Physiology, Sleep and Performance Research Center, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, United States
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9
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Bauer HF, Delling JP, Bockmann J, Boeckers TM, Schön M. Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders. Front Behav Neurosci 2023; 16:1051175. [PMID: 36699652 PMCID: PMC9868822 DOI: 10.3389/fnbeh.2022.1051175] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 12/05/2022] [Indexed: 01/11/2023] Open
Abstract
Individuals with a SHANK3-related neurodevelopmental disorder, also termed Phelan-McDermid syndrome or abbreviated as PMS, exhibit significant global developmental delay, language impairment, and muscular hypotonia. Also common are repetitive behaviors and altered social interactions, in line with a diagnosis of autism spectrum disorders. This study investigated the developmental aspect of autism-related behaviors and other phenotypes in a Shank3-transgenic mouse model. The animals underwent two sets of identical behavioral experiments, spanning motor skills, social and repetitive behavior, and cognition: baseline began at 5 weeks of age, corresponding to human adolescence, and the follow-up was initiated when aged 13 weeks, resembling early adulthood in humans. Interestingly, the animals displayed relatively stable phenotypes. Moreover, motor coordination and endurance were impaired, while muscle strength was unchanged. Surprisingly, the animals displayed only minor impairments in social behavior, but pronounced stereotypic and repetitive behaviors. Some behavioral tests indicated increased avoidance and anxiety. While spatial learning and memory were unchanged, knockout animals displayed slightly impaired cognitive flexibility. Female animals had similar abnormalities as males in the paradigms testing avoidance, anxiety, and cognition, but were less pathological in motor function and repetitive behavior. In all test paradigms, heterozygous Shank3 knockout animals had either no abnormal or a milder phenotype. Accurate characterization of animal models for genetic diseases is a prerequisite for understanding the pathophysiology. This is subsequently the basis for finding suitable and, ideally, translational biomarkers for therapeutic approaches and, thereby reducing the number of animals needed for preclinical trials.
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Affiliation(s)
- Helen Friedericke Bauer
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany,International Graduate School in Molecular Medicine Ulm, Ulm University, Ulm, Germany
| | | | - Jürgen Bockmann
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
| | - Tobias M. Boeckers
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany,Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm Site, Ulm, Germany,*Correspondence: Tobias M. Boeckers,
| | - Michael Schön
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany,Michael Schön,
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10
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Klomp AJ, Plumb A, Mehr JB, Madencioglu DA, Wen H, Williams AJ. Neuronal deletion of Ca V1.2 is associated with sex-specific behavioral phenotypes in mice. Sci Rep 2022; 12:22152. [PMID: 36550186 PMCID: PMC9780340 DOI: 10.1038/s41598-022-26504-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
The gene CACNA1C, which encodes the pore forming subunit of the L-type calcium channel CaV1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of CaV1.2 results in cognitive, affective, and motor deficits. Most previous work has either included non-neuronal cell populations (haploinsufficient and Nestin-Cre) or investigated a discrete neuronal cell population (e.g. CaMKII-Cre, Drd1-Cre), but few studies have examined the effects of more broad neuron-specific deletion of CaV1.2. Additionally, most of these studies did not evaluate for sex-specific effects or used only male animals. Here, we sought to clarify whether there are sex-specific behavioral consequences of neuron-specific deletion of CaV1.2 (neuronal CaV1.2 cKO) using Syn1-Cre-mediated conditional deletion. We found that neuronal CaV1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal CaV1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal CaV1.2 cKO mice did not display normal social preference, whereas female neuronal CaV1.2 cKO mice did. Neuronal CaV1.2 cKO mice displayed impaired associative learning in both sexes, as well as normal anxiety-like behavior and hedonic capacity. We conclude that deletion of neuronal CaV1.2 alters motor performance, acoustic startle reflex, and social behaviors in a sex-specific manner, while associative learning deficits generalize across sexes. Our data provide evidence for both sex-specific and sex-independent phenotypes related to neuronal expression of CaV1.2.
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Affiliation(s)
- Annette J Klomp
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Ashley Plumb
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
| | - Jacqueline B Mehr
- Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA
- Brain Health Institute, Rutgers University, Piscataway, NJ, USA
| | - Deniz A Madencioglu
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Hsiang Wen
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA
| | - Aislinn J Williams
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA.
- Department of Psychiatry, University of Iowa, Iowa City, IA, USA.
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11
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Lee K, Mills Z, Cheung P, Cheyne JE, Montgomery JM. The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders. Pharmaceuticals (Basel) 2022; 16:ph16010001. [PMID: 36678498 PMCID: PMC9866730 DOI: 10.3390/ph16010001] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
NMDA-type glutamate receptors are critical for synaptic plasticity in the central nervous system. Their unique properties and age-dependent arrangement of subunit types underpin their role as a coincidence detector of pre- and postsynaptic activity during brain development and maturation. NMDAR function is highly modulated by zinc, which is co-released with glutamate and concentrates in postsynaptic spines. Both NMDARs and zinc have been strongly linked to autism spectrum disorders (ASDs), suggesting that NMDARs are an important player in the beneficial effects observed with zinc in both animal models and children with ASDs. Significant evidence is emerging that these beneficial effects occur via zinc-dependent regulation of SHANK proteins, which form the backbone of the postsynaptic density. For example, dietary zinc supplementation enhances SHANK2 or SHANK3 synaptic recruitment and rescues NMDAR deficits and hypofunction in Shank3ex13-16-/- and Tbr1+/- ASD mice. Across multiple studies, synaptic changes occur in parallel with a reversal of ASD-associated behaviours, highlighting the zinc-dependent regulation of NMDARs and glutamatergic synapses as therapeutic targets for severe forms of ASDs, either pre- or postnatally. The data from rodent models set a strong foundation for future translational studies in human cells and people affected by ASDs.
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12
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Purushotham SS, Reddy NMN, D'Souza MN, Choudhury NR, Ganguly A, Gopalakrishna N, Muddashetty R, Clement JP. A perspective on molecular signalling dysfunction, its clinical relevance and therapeutics in autism spectrum disorder. Exp Brain Res 2022; 240:2525-2567. [PMID: 36063192 DOI: 10.1007/s00221-022-06448-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 08/18/2022] [Indexed: 11/29/2022]
Abstract
Intellectual disability (ID) and autism spectrum disorder (ASD) are neurodevelopmental disorders that have become a primary clinical and social concern, with a prevalence of 2-3% in the population. Neuronal function and behaviour undergo significant malleability during the critical period of development that is found to be impaired in ID/ASD. Human genome sequencing studies have revealed many genetic variations associated with ASD/ID that are further verified by many approaches, including many mouse and other models. These models have facilitated the identification of fundamental mechanisms underlying the pathogenesis of ASD/ID, and several studies have proposed converging molecular pathways in ASD/ID. However, linking the mechanisms of the pathogenic genes and their molecular characteristics that lead to ID/ASD has progressed slowly, hampering the development of potential therapeutic strategies. This review discusses the possibility of recognising the common molecular causes for most ASD/ID based on studies from the available models that may enable a better therapeutic strategy to treat ID/ASD. We also reviewed the potential biomarkers to detect ASD/ID at early stages that may aid in diagnosis and initiating medical treatment, the concerns with drug failure in clinical trials, and developing therapeutic strategies that can be applied beyond a particular mutation associated with ASD/ID.
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Affiliation(s)
- Sushmitha S Purushotham
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Neeharika M N Reddy
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Michelle Ninochka D'Souza
- Centre for Brain Research, Indian Institute of Science Campus, CV Raman Avenue, Bangalore, 560 012, India.,The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bangalore, 560064, India
| | - Nilpawan Roy Choudhury
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Anusa Ganguly
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Niharika Gopalakrishna
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India
| | - Ravi Muddashetty
- Centre for Brain Research, Indian Institute of Science Campus, CV Raman Avenue, Bangalore, 560 012, India.,The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bangalore, 560064, India
| | - James P Clement
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, 560064, India.
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13
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Wan L, Liu D, Xiao WB, Zhang BX, Yan XX, Luo ZH, Xiao B. Association of SHANK Family with Neuropsychiatric Disorders: An Update on Genetic and Animal Model Discoveries. Cell Mol Neurobiol 2022; 42:1623-1643. [PMID: 33595806 PMCID: PMC11421742 DOI: 10.1007/s10571-021-01054-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/02/2021] [Indexed: 12/14/2022]
Abstract
The Shank family proteins are enriched at the postsynaptic density (PSD) of excitatory glutamatergic synapses. They serve as synaptic scaffolding proteins and appear to play a critical role in the formation, maintenance and functioning of synapse. Increasing evidence from genetic association and animal model studies indicates a connection of SHANK genes defects with the development of neuropsychiatric disorders. In this review, we first update the current understanding of the SHANK family genes and their encoded protein products. We then denote the literature relating their alterations to the risk of neuropsychiatric diseases. We further review evidence from animal models that provided molecular insights into the biological as well as pathogenic roles of Shank proteins in synapses, and the potential relationship to the development of abnormal neurobehavioral phenotypes.
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Affiliation(s)
- Lily Wan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Du Liu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Taikang Tongji Hospital, Wuhan, 430050, Hubei, China
| | - Wen-Biao Xiao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Bo-Xin Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiao-Xin Yan
- Department of Anatomy and Neurobiology, Central South University, Changsha, 410013, Hunan, China
| | - Zhao-Hui Luo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Bo Xiao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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14
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Samandra R, Haque ZZ, Rosa MGP, Mansouri FA. The marmoset as a model for investigating the neural basis of social cognition in health and disease. Neurosci Biobehav Rev 2022; 138:104692. [PMID: 35569579 DOI: 10.1016/j.neubiorev.2022.104692] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/05/2022] [Accepted: 05/09/2022] [Indexed: 01/23/2023]
Abstract
Social-cognitive processes facilitate the use of environmental cues to understand others, and to be understood by others. Animal models provide vital insights into the neural underpinning of social behaviours. To understand social cognition at even deeper behavioural, cognitive, neural, and molecular levels, we need to develop more representative study models, which allow testing of novel hypotheses using human-relevant cognitive tasks. Due to their cooperative breeding system and relatively small size, common marmosets (Callithrix jacchus) offer a promising translational model for such endeavours. In addition to having social behavioural patterns and group dynamics analogous to those of humans, marmosets have cortical brain areas relevant for the mechanistic analysis of human social cognition, albeit in simplified form. Thus, they are likely suitable animal models for deciphering the physiological processes, connectivity and molecular mechanisms supporting advanced cognitive functions. Here, we review findings emerging from marmoset social and behavioural studies, which have already provided significant insights into executive, motivational, social, and emotional dysfunction associated with neurological and psychiatric disorders.
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Affiliation(s)
- Ranshikha Samandra
- Cognitive Neuroscience Laboratory, Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Zakia Z Haque
- Cognitive Neuroscience Laboratory, Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
| | - Marcello G P Rosa
- Department of Physiology and Neuroscience Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia; ARC Centre for Integrative Brain Function, Monash University, Australia.
| | - Farshad Alizadeh Mansouri
- Cognitive Neuroscience Laboratory, Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia; ARC Centre for Integrative Brain Function, Monash University, Australia.
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15
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Hu L, Zhang L. Adult neural stem cells and schizophrenia. World J Stem Cells 2022; 14:219-230. [PMID: 35432739 PMCID: PMC8968214 DOI: 10.4252/wjsc.v14.i3.219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a devastating and complicated mental disorder accompanied by variable positive and negative symptoms and cognitive deficits. Although many genetic risk factors have been identified, SCZ is also considered as a neurodevelopmental disorder. Elucidation of the pathogenesis and the development of treatment is challenging because complex interactions occur between these genetic risk factors and environment in essential neurodevelopmental processes. Adult neural stem cells share a lot of similarities with embryonic neural stem cells and provide a promising model for studying neuronal development in adulthood. These adult neural stem cells also play an important role in cognitive functions including temporal and spatial memory encoding and context discrimination, which have been shown to be closely linked with many psychiatric disorders, such as SCZ. Here in this review, we focus on the SCZ risk genes and the key components in related signaling pathways in adult hippocampal neural stem cells and summarize their roles in adult neurogenesis and animal behaviors. We hope that this would be helpful for the understanding of the contribution of dysregulated adult neural stem cells in the pathogenesis of SCZ and for the identification of potential therapeutic targets, which could facilitate the development of novel medication and treatment.
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Affiliation(s)
- Ling Hu
- Department of Laboratory Animal Science and Institutes of Brain Science, Fudan University, Shanghai 200032, China
| | - Lei Zhang
- Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center) and Department of Anatomy and Neurobiology, Tongji University School of Medicine, Shanghai 200092, China
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16
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17
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Delling JP, Boeckers TM. Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications. J Neurodev Disord 2021; 13:55. [PMID: 34784886 PMCID: PMC8594088 DOI: 10.1186/s11689-021-09397-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. MAIN TEXT This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. CONCLUSIONS Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors.
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Affiliation(s)
- Jan Philipp Delling
- Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, Ulm, 89081, Germany.
| | - Tobias M Boeckers
- Institute for Anatomy and Cell Biology, Ulm University, Albert-Einstein-Allee 11, Ulm, 89081, Germany. .,Ulm Site, DZNE, Ulm, Germany.
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18
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Mehta R, Bhandari R, Kuhad A. Effects of catechin on a rodent model of autism spectrum disorder: implications for the role of nitric oxide in neuroinflammatory pathway. Psychopharmacology (Berl) 2021; 238:3249-3271. [PMID: 34448020 DOI: 10.1007/s00213-021-05941-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 07/20/2021] [Indexed: 11/27/2022]
Abstract
AIM The present research work aims at deciphering the involvement of nitric oxide pathway and its modulation by ( ±)catechin hydrate in experimental paradigm of autism spectrum disorders (ASD). METHOD An intracerebroventricular infusion of 4 μl of 1 M propanoic acid was given in the anterior region of the lateral ventricle to induce autism-like phenotype in male rats. Oral administration of ( ±)catechin hydrate (25, 50, and 100 mg/kg) was initiated from the 3rd day lasting till the 28th day. L-NAME (50 mg/kg) and L-arginine (800 mg/kg) were also given individually as well as in combination to explore the ability of ( ±)catechin hydrate to act via nitric oxide pathway. Behavior test for sociability, stereotypy, anxiety, depression, and novelty, repetitive, and perseverative behavior was carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and levels of mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To evaluate the involvement of nitric oxide pathway, the levels of iNOS and homocysteine were estimated. RESULTS Treatment with ( ±)catechin hydrate significantly ameliorated behavioral, biochemical, neurological, and molecular deficits. Hence, ( ±)catechin hydrate has potential to be used as neurotherapeutic agent in ASD targeting nitric oxide pathway-mediated oxidative and nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway. CONCLUSION The evaluation of the levels of iNOS and homocysteine conclusively establishes the role of nitric oxide pathway in causing behavioral, biochemical, and molecular deficits and the beneficial effect of ( ±)catechin hydrate in restoring these alterations.
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Affiliation(s)
- Rishab Mehta
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, 160 014, India
| | - Ranjana Bhandari
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, 160 014, India.
| | - Anurag Kuhad
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, 160 014, India.
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19
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Gzielo K, Nikiforuk A. Astroglia in Autism Spectrum Disorder. Int J Mol Sci 2021; 22:11544. [PMID: 34768975 PMCID: PMC8583956 DOI: 10.3390/ijms222111544] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/13/2021] [Accepted: 10/21/2021] [Indexed: 01/12/2023] Open
Abstract
Autism spectrum disorder (ASD) is an umbrella term encompassing several neurodevelopmental disorders such as Asperger syndrome or autism. It is characterised by the occurrence of distinct deficits in social behaviour and communication and repetitive patterns of behaviour. The symptoms may be of different intensity and may vary in types. Risk factors for ASD include disturbed brain homeostasis, genetic predispositions, or inflammation during the prenatal period caused by viruses or bacteria. The number of diagnosed cases is growing, but the main cause and mechanism leading to ASD is still uncertain. Recent findings from animal models and human cases highlight the contribution of glia to the ASD pathophysiology. It is known that glia cells are not only "gluing" neurons together but are key players participating in different processes crucial for proper brain functioning, including neurogenesis, synaptogenesis, inflammation, myelination, proper glutamate processing and many others. Despite the prerequisites for the involvement of glia in the processes related to the onset of autism, there are far too little data regarding the engagement of these cells in the development of ASD.
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Affiliation(s)
- Kinga Gzielo
- Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Behavioral Neuroscience and Drug Development, 12 Smętna Street, 31-343 Kraków, Poland;
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20
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Mehta R, Bhandari R, Kuhad A. Exploring nordihydroguaretic acid (NDGA) as a plausible neurotherapeutic in the experimental paradigm of autism spectrum disorders targeting nitric oxide pathway. Metab Brain Dis 2021; 36:1833-1857. [PMID: 34363573 DOI: 10.1007/s11011-021-00811-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 07/26/2021] [Indexed: 12/14/2022]
Abstract
The present study investigates the neuro-protective ability of nordihydroguaretic acid (NDGA) in the experimental paradigm of autism spectrum disorders (ASD) and further decipher the nitric oxide pathway's role in its proposed action. An intracerebroventricular infusion of 4 μl of 1 M PPA was given in the lateral ventricle's anterior region to induce autism-like phenotype in male rats. Oral administration of NDGA (5, 10 & 15 mg/kg) was initiated from the 3rd day lasting till the 28th day. L-NAME (50 mg/kg) and L-Arginine (800 mg/kg) were also given individually and combined to explore NDGA's ability to act via the nitric oxide pathway. Behavior tests for sociability, stereotypy, anxiety, depression, novelty, repetitive and perseverative behavior were carried out between the 14th and 28th day. On the 29th day, animals were sacrificed, and mitochondrial complexes and oxidative stress parameters were evaluated. We also estimated the levels of neuroinflammatory and apoptotic markers such as TNF-α, IL-6, NF-κB, IFN-γ, HSP-70, and caspase-3. To assess the involvement of the nitric oxide pathway, levels of iNOS and homocysteine were estimated. Treatment with NDGA significantly restored behavioral, biochemical, neurological, and molecular deficits. Hence, NDGA can be used as a neurotherapeutic agent in ASD. Targeting nitric oxide pathway mediated oxidative & nitrosative stress responsible for behavioral, biochemical, and molecular alterations via modulating nitric oxide pathway. The evaluation of iNOS and homocysteine levels conclusively establishes the nitric oxide pathway's role in causing behavioral, biochemical & molecular deficits and NDGA's beneficial effect in restoring these alterations.
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Affiliation(s)
- Rishab Mehta
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, 160 014, India
| | - Ranjana Bhandari
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, 160 014, India.
| | - Anurag Kuhad
- Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, 160 014, India.
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21
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Wan L, Ai JQ, Yang C, Jiang J, Zhang QL, Luo ZH, Huang RJ, Tu T, Pan A, Tu E, Manavis J, Xiao B, Yan XX. Expression of the Excitatory Postsynaptic Scaffolding Protein, Shank3, in Human Brain: Effect of Age and Alzheimer's Disease. Front Aging Neurosci 2021; 13:717263. [PMID: 34504419 PMCID: PMC8421777 DOI: 10.3389/fnagi.2021.717263] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 07/26/2021] [Indexed: 12/14/2022] Open
Abstract
Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer’s disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.
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Affiliation(s)
- Lily Wan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Jia-Qi Ai
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China
| | - Chen Yang
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China
| | - Juan Jiang
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China
| | - Qi-Lei Zhang
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China
| | - Zhao-Hui Luo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Rou-Jie Huang
- Medical Doctor Program, Xiangya School of Medicine, Central South University, Changsha, China
| | - Tian Tu
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Aihua Pan
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China
| | - Ewen Tu
- Department of Neurology, Brain Hospital of Hunan Province, Changsha, China
| | - Jim Manavis
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Bo Xiao
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiao-Xin Yan
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China
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22
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Yang CY, Hung YC, Cheng KH, Ling P, Hsu KS. Loss of CC2D1A in Glutamatergic Neurons Results in Autistic-Like Features in Mice. Neurotherapeutics 2021; 18:2021-2039. [PMID: 34132974 PMCID: PMC8608959 DOI: 10.1007/s13311-021-01072-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2021] [Indexed: 02/04/2023] Open
Abstract
Biallelic loss-of-function mutations in Coiled-coil and C2 domain containing 1A (CC2D1A) cause autosomal recessive intellectual disability, sometimes comorbid with other neurodevelopmental disabilities, such as autism spectrum disorder (ASD) and seizures. We recently reported that conditional deletion of Cc2d1a in glutamatergic neurons of the postnatal mouse forebrain leads to impaired hippocampal synaptic plasticity and cognitive function. However, the pathogenic origin of the autistic features of CC2D1A deficiency remains elusive. Here, we confirmed that CC2D1A is highly expressed in the cortical zones during embryonic development. Taking advantage of Cre-LoxP-mediated gene deletion strategy, we generated a novel line of Cc2d1a conditional knockout (cKO) mice by crossing floxed Cc2d1a mice with Emx1-Cre mice, in which CC2D1A is ablated specifically in glutamatergic neurons throughout all embryonic and adult stages. We found that CC2D1A deletion leads to a trend toward decreased number of cortical progenitor cells at embryonic day 12.5 and alters the cortical thickness on postnatal day 10. In addition, male Cc2d1a cKO mice display autistic-like phenotypes including self-injurious repetitive grooming and aberrant social interactions. Loss of CC2D1A also results in decreased complexity of apical dendritic arbors of medial prefrontal cortex (mPFC) layer V pyramidal neurons and increased synaptic excitation/inhibition (E/I) ratio in the mPFC. Notably, chronic treatment with minocycline rescues behavioral and morphological abnormalities, as well as E/I changes, in male Cc2d1a cKO mice. Together, these findings indicate that male Cc2d1a cKO mice recapitulate autistic-like phenotypes of human disorder and suggest that minocycline has both structural and functional benefits in treating ASD.
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Affiliation(s)
- Cheng-Yi Yang
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yu-Chieh Hung
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Kuan-Hsiang Cheng
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Pin Ling
- Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Kuei-Sen Hsu
- Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
- Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan, 70101, Taiwan.
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23
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Xu J, Marshall JJ, Kraniotis S, Nomura T, Zhu Y, Contractor A. Genetic disruption of Grm5 causes complex alterations in motor activity, anxiety and social behaviors. Behav Brain Res 2021; 411:113378. [PMID: 34029630 DOI: 10.1016/j.bbr.2021.113378] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 05/11/2021] [Accepted: 05/19/2021] [Indexed: 12/14/2022]
Abstract
Autism is a neurodevelopmental disorder characterized by impaired social interactions and restricted and repetitive behaviors. Although group 1 metabotropic glutamate receptors (mGluRs), and in particular mGluR5, have been extensively proposed as potential targets for intervention in autism and other neurodevelopmental disorders, there has not been a comprehensive analysis of the effect of mGluR5 loss on behaviors typically assessed in autism mouse models thought to be correlates of behavioral symptoms of human disorders. Here we present a behavioral characterization of mice with complete or partial loss of mGluR5 (homozygous or heterozygous null mutations in Grm5 gene). We tested several autism related behaviors including social interaction, repetitive grooming, digging and locomotor behaviors. We found that digging and marble burying behaviors were almost completely abolished in mGluR5 ko mice, although self-grooming was not altered. Social interaction was impaired in ko but not in heterozygote (het) mice. In tests of locomotor activity and anxiety related behaviors, mGluR5 ko mice exhibited hyperactivity and reduced anxiety in the open field test but unexpectedly, showed hypoactivity in the elevated zero-maze test. There was no impairment in motor learning in the accelerating rotarod in both ko and het mutant. Together these results provide support for the importance of mGluR5 in motor and social behaviors that are specifically affected in autism disorders.
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Affiliation(s)
- Jian Xu
- Department of Physiology, Northwestern University Feinberg School of Medicine, United States.
| | - John J Marshall
- Department of Physiology, Northwestern University Feinberg School of Medicine, United States
| | - Stephen Kraniotis
- Department of Physiology, Northwestern University Feinberg School of Medicine, United States
| | - Toshihiro Nomura
- Department of Physiology, Northwestern University Feinberg School of Medicine, United States
| | - Yongling Zhu
- Department of Physiology, Northwestern University Feinberg School of Medicine, United States
| | - Anis Contractor
- Department of Physiology, Northwestern University Feinberg School of Medicine, United States; Department of Neurobiology, Weinberg College of Arts and Sciences, Northwestern University, Chicago, IL, 60611, United States.
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Kessi M, Chen B, Peng J, Yan F, Yang L, Yin F. Calcium channelopathies and intellectual disability: a systematic review. Orphanet J Rare Dis 2021; 16:219. [PMID: 33985586 PMCID: PMC8120735 DOI: 10.1186/s13023-021-01850-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 05/04/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. MAIN BODY A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. CONCLUSION Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.
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Affiliation(s)
- Miriam Kessi
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
- Kilimanjaro Christian Medical University College, Moshi, Tanzania
- Mawenzi Regional Referral Hospital, Moshi, Tanzania
| | - Baiyu Chen
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
| | - Jing Peng
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
| | - Fangling Yan
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
| | - Lifen Yang
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China
| | - Fei Yin
- Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Hunan Intellectual and Developmental Disabilities Research Center, Changsha, Hunan, China.
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25
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Hopp SC. Targeting microglia L-type voltage-dependent calcium channels for the treatment of central nervous system disorders. J Neurosci Res 2021; 99:141-162. [PMID: 31997405 PMCID: PMC9394523 DOI: 10.1002/jnr.24585] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/03/2020] [Accepted: 01/08/2020] [Indexed: 12/14/2022]
Abstract
Calcium (Ca2+ ) is a ubiquitous mediator of a multitude of cellular functions in the central nervous system (CNS). Intracellular Ca2+ is tightly regulated by cells, including entry via plasma membrane Ca2+ permeable channels. Of specific interest for this review are L-type voltage-dependent Ca2+ channels (L-VDCCs), due to their pleiotropic role in several CNS disorders. Currently, there are numerous approved drugs that target L-VDCCs, including dihydropyridines. These drugs are safe and effective for the treatment of humans with cardiovascular disease and may also confer neuroprotection. Here, we review the potential of L-VDCCs as a target for the treatment of CNS disorders with a focus on microglia L-VDCCs. Microglia, the resident immune cells of the brain, have attracted recent attention for their emerging inflammatory role in several CNS diseases. Intracellular Ca2+ regulates microglia transition from a resting quiescent state to an "activated" immune-effector state and is thus a valuable target for manipulation of microglia phenotype. We will review the literature on L-VDCC expression and function in the CNS and on microglia in vitro and in vivo and explore the therapeutic landscape of L-VDCC-targeting agents at present and future challenges in the context of Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropsychiatric diseases, and other CNS disorders.
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Affiliation(s)
- Sarah C. Hopp
- Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
- Department of Pharmacology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA
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26
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Santana-Coelho D, Layne-Colon D, Valdespino R, Ross CC, Tardif SD, O'Connor JC. Advancing Autism Research From Mice to Marmosets: Behavioral Development of Offspring Following Prenatal Maternal Immune Activation. Front Psychiatry 2021; 12:705554. [PMID: 34421684 PMCID: PMC8377364 DOI: 10.3389/fpsyt.2021.705554] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/07/2021] [Indexed: 12/31/2022] Open
Abstract
Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.
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Affiliation(s)
- Danielle Santana-Coelho
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Donna Layne-Colon
- Southwest National Primate Center, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Roslyn Valdespino
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Corinna C Ross
- Southwest National Primate Center, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Suzette D Tardif
- Southwest National Primate Center, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Jason C O'Connor
- Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States.,Audie L. Murphy Veterans Affairs, South Texas Veterans Health System, San Antonio, TX, United States
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27
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Endres D, Decher N, Röhr I, Vowinkel K, Domschke K, Komlosi K, Tzschach A, Gläser B, Schiele MA, Runge K, Süß P, Schuchardt F, Nickel K, Stallmeyer B, Rinné S, Schulze-Bahr E, Tebartz van Elst L. New Cav1.2 Channelopathy with High-Functioning Autism, Affective Disorder, Severe Dental Enamel Defects, a Short QT Interval, and a Novel CACNA1C Loss-Of-Function Mutation. Int J Mol Sci 2020; 21:ijms21228611. [PMID: 33203140 PMCID: PMC7696251 DOI: 10.3390/ijms21228611] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 11/04/2020] [Accepted: 11/07/2020] [Indexed: 12/12/2022] Open
Abstract
Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.
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Affiliation(s)
- Dominique Endres
- Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.R.); (K.N.); (L.T.v.E.)
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.D.); (M.A.S.)
- Correspondence: ; Tel.: +49-761-270-66360
| | - Niels Decher
- Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany; (N.D.); (I.R.); (K.V.); (S.R.)
| | - Isabell Röhr
- Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany; (N.D.); (I.R.); (K.V.); (S.R.)
| | - Kirsty Vowinkel
- Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany; (N.D.); (I.R.); (K.V.); (S.R.)
| | - Katharina Domschke
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.D.); (M.A.S.)
- Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Katalin Komlosi
- Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (K.K.); (A.T.); (B.G.)
| | - Andreas Tzschach
- Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (K.K.); (A.T.); (B.G.)
| | - Birgitta Gläser
- Institute of Human Genetics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (K.K.); (A.T.); (B.G.)
| | - Miriam A. Schiele
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.D.); (M.A.S.)
| | - Kimon Runge
- Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.R.); (K.N.); (L.T.v.E.)
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.D.); (M.A.S.)
| | - Patrick Süß
- Department of Molecular Neurology, University Hospital Erlangen, 91054 Erlangen, Germany;
| | - Florian Schuchardt
- Department of Neurology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
| | - Kathrin Nickel
- Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.R.); (K.N.); (L.T.v.E.)
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.D.); (M.A.S.)
| | - Birgit Stallmeyer
- Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany; (B.S.); (E.S.-B.)
| | - Susanne Rinné
- Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior-Philipps-University Marburg, 35037 Marburg, Germany; (N.D.); (I.R.); (K.V.); (S.R.)
| | - Eric Schulze-Bahr
- Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Münster, 48149 Münster, Germany; (B.S.); (E.S.-B.)
| | - Ludger Tebartz van Elst
- Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.R.); (K.N.); (L.T.v.E.)
- Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; (K.D.); (M.A.S.)
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28
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Peixoto RT, Chantranupong L, Hakim R, Levasseur J, Wang W, Merchant T, Gorman K, Budnik B, Sabatini BL. Abnormal Striatal Development Underlies the Early Onset of Behavioral Deficits in Shank3B -/- Mice. Cell Rep 2020; 29:2016-2027.e4. [PMID: 31722214 PMCID: PMC6889826 DOI: 10.1016/j.celrep.2019.10.021] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 07/12/2019] [Accepted: 10/04/2019] [Indexed: 11/17/2022] Open
Abstract
The neural substrates and pathophysiological mechanisms underlying the onset of cognitive and motor deficits in autism spectrum disorders (ASDs) remain unclear. Mutations in ASD-associated SHANK3 in mice (Shank3B−/−) result in the accelerated maturation of corticostriatal circuits during the second and third postnatal weeks. Here, we show that during this period, there is extensive remodeling of the striatal synaptic proteome and a developmental switch in glutamatergic synaptic plasticity induced by cortical hyperactivity in striatal spiny projection neurons (SPNs). Behavioral abnormalities in Shank3B−/− mice emerge during this stage and are ameliorated by normalizing excitatory synapse connectivity in medial striatal regions by the downregulation of PKA activity. These results suggest that the abnormal postnatal development of striatal circuits is implicated in the onset of behavioral deficits in Shank3B−/− mice and that modulation of postsynaptic PKA activity can be used to regulate corticostriatal drive in developing SPNs of mouse models of ASDs and other neurodevelopmental disorders. Peixoto et al. show that the onset of behavioral deficits in Shank3B−/− mice occurs during early postnatal development and that these can be ameliorated by reducing the glutamatergic synaptic drive in medial regions of the striatum by the downregulation of PKA activity.
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Affiliation(s)
- Rui Tiago Peixoto
- Department of Psychiatry, University of Pittsburgh, 450 Technology Dr, Pittsburgh, PA 15219, USA; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA.
| | - Lynne Chantranupong
- Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA
| | - Richard Hakim
- Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA
| | - James Levasseur
- Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA
| | - Wengang Wang
- Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA
| | - Tasha Merchant
- Department of Psychiatry, University of Pittsburgh, 450 Technology Dr, Pittsburgh, PA 15219, USA; Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA
| | - Kelly Gorman
- Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA
| | - Bogdan Budnik
- Mass Spectrometry and Proteomic Laboratory, FAS Division of Science, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA
| | - Bernardo Luis Sabatini
- Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, 220 Longwood Ave., Boston, MA 02115, USA
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29
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Kabitzke P, Morales D, He D, Cox K, Sutphen J, Thiede L, Sabath E, Hanania T, Biemans B, Brunner D. Mouse model systems of autism spectrum disorder: Replicability and informatics signature. GENES BRAIN AND BEHAVIOR 2020; 19:e12676. [PMID: 32445272 PMCID: PMC7540461 DOI: 10.1111/gbb.12676] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 05/13/2020] [Accepted: 05/20/2020] [Indexed: 12/28/2022]
Abstract
Phenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter- and intra-laboratory replicability, particularly in behavioral domains such as social and cognitive function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies of five genetic mouse model systems of ASD. To assess the intra-laboratory robustness of previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three-yearlong effort using informatics techniques to assess commonalities and differences. Our results showed high intra-laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle but pivotal differences in testing conditions, housing enrichment, or background strains and less so on the variability of the behavioral phenotypes. The overall informatics analysis suggests that in our behavioral assays we can separate the set of tested mouse model system into two main classes that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept.
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Affiliation(s)
- Patricia Kabitzke
- PsychoGenics, Inc., Paramus, New Jersey, USA.,The Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Diana Morales
- PsychoGenics, Inc., Paramus, New Jersey, USA.,Pfizer, Pearl River, NY, USA
| | - Dansha He
- PsychoGenics, Inc., Paramus, New Jersey, USA
| | | | - Jane Sutphen
- PsychoGenics, Inc., Paramus, New Jersey, USA.,Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Lucinda Thiede
- PsychoGenics, Inc., Paramus, New Jersey, USA.,Boehringer Ingelheim, Ridgefield, CT, USA
| | - Emily Sabath
- PsychoGenics, Inc., Paramus, New Jersey, USA.,JRS Pharma, Patterson, NY, USA
| | | | | | - Daniela Brunner
- PsychoGenics, Inc., Paramus, New Jersey, USA.,Department of Psychiatry, Columbia University, New York, NY, USA
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30
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Berg EL, Pride MC, Petkova SP, Lee RD, Copping NA, Shen Y, Adhikari A, Fenton TA, Pedersen LR, Noakes LS, Nieman BJ, Lerch JP, Harris S, Born HA, Peters MM, Deng P, Cameron DL, Fink KD, Beitnere U, O'Geen H, Anderson AE, Dindot SV, Nash KR, Weeber EJ, Wöhr M, Ellegood J, Segal DJ, Silverman JL. Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome. Transl Psychiatry 2020; 10:39. [PMID: 32066685 PMCID: PMC7026078 DOI: 10.1038/s41398-020-0720-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 12/17/2019] [Accepted: 01/02/2020] [Indexed: 12/17/2022] Open
Abstract
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.
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Affiliation(s)
- E L Berg
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - M C Pride
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - S P Petkova
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - R D Lee
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - N A Copping
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - Y Shen
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - A Adhikari
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - T A Fenton
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - L R Pedersen
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA
| | - L S Noakes
- Mouse Imaging Centre, Toronto Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, Canada
| | - B J Nieman
- Mouse Imaging Centre, Toronto Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, Canada
| | - J P Lerch
- Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK
| | - S Harris
- Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, TX, USA
| | - H A Born
- Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, TX, USA
| | - M M Peters
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - P Deng
- Stem Cell Program, Institute for Regenerative Cures, and Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - D L Cameron
- Stem Cell Program, Institute for Regenerative Cures, and Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - K D Fink
- Stem Cell Program, Institute for Regenerative Cures, and Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA
| | - U Beitnere
- MIND Institute, Genome Center, and Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
| | - H O'Geen
- MIND Institute, Genome Center, and Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
| | - A E Anderson
- Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, TX, USA
| | - S V Dindot
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - K R Nash
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - E J Weeber
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA
| | - M Wöhr
- Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Marburg, Germany
| | - J Ellegood
- Mouse Imaging Centre, Toronto Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, Canada
| | - D J Segal
- MIND Institute, Genome Center, and Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
| | - J L Silverman
- MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA.
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31
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Foxe JJ, Molholm S, Baudouin SJ, Wallace MT. Explorations and perspectives on the neurobiological bases of autism spectrum disorder. Eur J Neurosci 2019; 47:488-496. [PMID: 29575230 DOI: 10.1111/ejn.13902] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- John J Foxe
- Department of Neuroscience, The Ernest J. Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.,The Cognitive Neurophysiology Laboratory, Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Sophie Molholm
- Department of Neuroscience, The Ernest J. Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.,The Cognitive Neurophysiology Laboratory, Departments of Pediatrics and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Mark T Wallace
- Center for Integrative and Cognitive Neuroscience, Vanderbilt University, Nashville, TN, USA
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32
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Andrade A, Brennecke A, Mallat S, Brown J, Gomez-Rivadeneira J, Czepiel N, Londrigan L. Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders. Int J Mol Sci 2019; 20:E3537. [PMID: 31331039 PMCID: PMC6679227 DOI: 10.3390/ijms20143537] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/12/2019] [Accepted: 07/13/2019] [Indexed: 12/23/2022] Open
Abstract
Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however, new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (CaVs). Calcium entering through CaVs is crucial for multiple neuronal processes. In this review, we will summarize recent findings that link CaVs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of CaVs structure, classification, function, expression and pharmacology. Next, we will summarize tools to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in CaV genes when available. Finally, we will review pharmacological evidence of the use of CaV modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of CaVs.
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Affiliation(s)
- Arturo Andrade
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA.
| | - Ashton Brennecke
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
| | - Shayna Mallat
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
| | - Julian Brown
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
| | | | - Natalie Czepiel
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
| | - Laura Londrigan
- Department of Biological Sciences, University of New Hampshire, Durham, NH 03824, USA
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33
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Redecker TM, Kisko TM, Schwarting RK, Wöhr M. Effects of Cacna1c haploinsufficiency on social interaction behavior and 50-kHz ultrasonic vocalizations in adult female rats. Behav Brain Res 2019; 367:35-52. [DOI: 10.1016/j.bbr.2019.03.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 03/03/2019] [Accepted: 03/15/2019] [Indexed: 01/28/2023]
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34
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Behavioral and neuroanatomical approaches in models of neurodevelopmental disorders: opportunities for translation. Curr Opin Neurol 2019; 31:126-133. [PMID: 29493556 DOI: 10.1097/wco.0000000000000537] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW This review highlights the invaluable contribution of in-vivo rodent models in dissecting the underlying neurobiology for numerous neurodevelopmental disorders. Currently, models are routinely generated with precision genomics and characterized for research on neurodevelopmental disorders. In order to impact translation, outcome measures that are translationally relevant are essential. This review emphasizes the importance of accurate neurobehavioral and anatomical analyses. RECENT FINDINGS Numerous well validated assays for testing alterations across behavioral domains with sensitivity and throughput have become important tools for studying the effects of genetic mutations on neurodevelopment. Recent work has highlighted relationships and links between behavioral outcomes and various anatomical metrics from neuroimaging via magnetic resonance. These readouts are biological markers and outcome measures for translational research and will be have important roles for genetic or pharmacologic intervention strategies. SUMMARY Combinatorial approaches that leverage translationally relevant behavior and neuroanatomy can be used to develop a platform for assessment of cutting edge preclinical models. Reliable, robust behavioral phenotypes in preclinical model systems, with clustering of brain disease will lead to well informed, precise biochemical mechanistic hypotheses. Ultimately, these steadfast workhorse techniques will accelerate the progress of developing and testing targeted treatments for multiple neurodevelopmental disorders.
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35
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Kisko TM, Braun MD, Michels S, Witt SH, Rietschel M, Culmsee C, Schwarting RKW, Wöhr M. Sex‐dependent effects of
Cacna1c
haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats. GENES BRAIN AND BEHAVIOR 2019; 19:e12552. [DOI: 10.1111/gbb.12552] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 12/22/2018] [Accepted: 12/26/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Theresa M. Kisko
- Behavioral Neuroscience, Experimental and Biological Psychology, Department of PsychologyPhilipps‐Universität Marburg Marburg Germany
| | - Moria D. Braun
- Behavioral Neuroscience, Experimental and Biological Psychology, Department of PsychologyPhilipps‐Universität Marburg Marburg Germany
| | - Susanne Michels
- Institute of Pharmacology and Clinical PharmacyPhilipps‐Universität Marburg Marburg Germany
| | - Stephanie H. Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine MannheimRuprecht‐Karls‐Universität Heidelberg Mannheim Germany
| | - Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine MannheimRuprecht‐Karls‐Universität Heidelberg Mannheim Germany
| | - Carsten Culmsee
- Institute of Pharmacology and Clinical PharmacyPhilipps‐Universität Marburg Marburg Germany
- Center for Mind, Brain, and Behavior (CMBB)Philipps‐Universität Marburg Marburg Germany
| | - Rainer K. W. Schwarting
- Behavioral Neuroscience, Experimental and Biological Psychology, Department of PsychologyPhilipps‐Universität Marburg Marburg Germany
- Center for Mind, Brain, and Behavior (CMBB)Philipps‐Universität Marburg Marburg Germany
| | - Markus Wöhr
- Behavioral Neuroscience, Experimental and Biological Psychology, Department of PsychologyPhilipps‐Universität Marburg Marburg Germany
- Center for Mind, Brain, and Behavior (CMBB)Philipps‐Universität Marburg Marburg Germany
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36
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Heppenheimer E, Brzeski KE, Hinton JW, Patterson BR, Rutledge LY, DeCandia AL, Wheeldon T, Fain SR, Hohenlohe PA, Kays R, White BN, Chamberlain MJ, vonHoldt BM. High genomic diversity and candidate genes under selection associated with range expansion in eastern coyote ( Canis latrans) populations. Ecol Evol 2018; 8:12641-12655. [PMID: 30619570 PMCID: PMC6309008 DOI: 10.1002/ece3.4688] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 10/10/2018] [Accepted: 10/15/2018] [Indexed: 12/29/2022] Open
Abstract
Range expansion is a widespread biological process, with well-described theoretical expectations associated with the colonization of novel ranges. However, comparatively few empirical studies address the genomic outcomes accompanying the genome-wide consequences associated with the range expansion process, particularly in recent or ongoing expansions. Here, we assess two recent and distinct eastward expansion fronts of a highly mobile carnivore, the coyote (Canis latrans), to investigate patterns of genomic diversity and identify variants that may have been under selection during range expansion. Using a restriction-associated DNA sequencing (RADseq), we genotyped 394 coyotes at 22,935 SNPs and found that overall population structure corresponded to their 19th century historical range and two distinct populations that expanded during the 20th century. Counter to theoretical expectations for populations to bottleneck during range expansions, we observed minimal evidence for decreased genomic diversity across coyotes sampled along either expansion front, which is likely due to hybridization with other Canis species. Furthermore, we identified 12 SNPs, located either within genes or putative regulatory regions, that were consistently associated with range expansion. Of these 12 genes, three (CACNA1C, ALK, and EPHA6) have putative functions related to dispersal, including habituation to novel environments and spatial learning, consistent with the expectations for traits under selection during range expansion. Although coyote colonization of eastern North America is well-publicized, this study provides novel insights by identifying genes associated with dispersal capabilities in coyotes on the two eastern expansion fronts.
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Affiliation(s)
| | - Kristin E. Brzeski
- Department of Ecology & Evolutionary BiologyPrinceton UniversityPrincetonNew Jersey
- School of Forest Resources and Environmental ScienceMichigan Technological UniversityHoughtonMichigan
| | - Joseph W. Hinton
- Warnell School of Forestry and Natural ResourcesUniversity of GeorgiaAthensGeorgia
| | - Brent R. Patterson
- Ontario Ministry of Natural Resources and ForestryPeterboroughOntarioCanada
- Trent UniversityPeterboroughOntario
| | - Linda Y. Rutledge
- Department of Ecology & Evolutionary BiologyPrinceton UniversityPrincetonNew Jersey
- Trent UniversityPeterboroughOntario
| | | | - Tyler Wheeldon
- Ontario Ministry of Natural Resources and ForestryPeterboroughOntarioCanada
- Trent UniversityPeterboroughOntario
| | | | - Paul A. Hohenlohe
- Department of Biological Sciences, Institute for Bioinformatics and Evolutionary StudiesUniversity of IdahoMoscowIdaho
| | - Roland Kays
- Department of Forestry and Environmental ResourcesNorth Carolina State UniversityRaleighNorth Carolina
- North Carolina Museum of Natural SciencesRaleighNorth Carolina
| | | | | | - Bridgett M. vonHoldt
- Department of Ecology & Evolutionary BiologyPrinceton UniversityPrincetonNew Jersey
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37
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Patel J, Lukkes JL, Shekhar A. Overview of genetic models of autism spectrum disorders. PROGRESS IN BRAIN RESEARCH 2018; 241:1-36. [PMID: 30447752 DOI: 10.1016/bs.pbr.2018.10.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Autism spectrum disorders (ASDs) are a group of neurodevelopment disorders that are characterized by heterogenous cognitive deficits and genetic factors. As more ASD risk genes are identified, genetic animal models have been developed to parse out the underlying neurobiological mechanisms of ASD. In this review, we discuss a subset of genetic models of ASD, focusing on those that have been widely studied and strongly linked to ASD. We focus our discussion of these models in the context of the theories and potential mechanisms of ASD, including disruptions in cell growth and proliferation, spine dynamics, synaptic transmission, excitation/inhibition balance, intracellular signaling, neuroinflammation, and behavior. In addition to ASD pathophysiology, we examine the limitations and challenges that genetic models pose for the study of ASD biology. We end with a review of innovative techniques and concepts of ASD pathology that can be further applied to and studied using genetic ASD models.
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Affiliation(s)
- Jheel Patel
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States; Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, IN, United States
| | - Jodi L Lukkes
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Anantha Shekhar
- Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States; Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indianapolis, IN, United States; Indiana Clinical and Translation Sciences Institute, Indiana University School of Medicine, Indianapolis, IN, United States.
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38
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Fourie C, Vyas Y, Lee K, Jung Y, Garner CC, Montgomery JM. Dietary Zinc Supplementation Prevents Autism Related Behaviors and Striatal Synaptic Dysfunction in Shank3 Exon 13-16 Mutant Mice. Front Cell Neurosci 2018; 12:374. [PMID: 30405356 PMCID: PMC6204368 DOI: 10.3389/fncel.2018.00374] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 10/01/2018] [Indexed: 12/27/2022] Open
Abstract
The SHANK family of synaptic proteins (SHANK1–3) are master regulators of the organizational structure of excitatory synapses in the brain. Mutations in SHANK1–3 are prevalent in patients with autism spectrum disorders (ASD), and loss of one copy of SHANK3 causes Phelan-McDermid Syndrome, a syndrome in which Autism occurs in >80% of cases. The synaptic stability of SHANK3 is highly regulated by zinc, driving the formation of postsynaptic protein complexes and increases in excitatory synaptic strength. As ASD-associated SHANK3 mutations retain responsiveness to zinc, here we investigated how increasing levels of dietary zinc could alter behavioral and synaptic deficits that occur with ASD. We performed behavioral testing together with cortico-striatal slice electrophysiology on a Shank3−/− mouse model of ASD (Shank3ex13–1616−/−), which displays ASD-related behaviors and structural and functional deficits at striatal synapses. We observed that 6 weeks of dietary zinc supplementation in Shank3ex13–16−/− mice prevented ASD-related repetitive and anxiety behaviors and deficits in social novelty recognition. Dietary zinc supplementation also increased the recruitment of zinc sensitive SHANK2 to synapses, reduced synaptic transmission specifically through N-methyl-D-aspartate (NMDA)-type glutamate receptors, reversed the slowed decay tau of NMDA receptor (NMDAR)-mediated currents and occluded long term potentiation (LTP) at cortico-striatal synapses. These data suggest that alterations in NMDAR function underlie the lack of NMDAR-dependent cortico-striatal LTP and contribute to the reversal of ASD-related behaviors such as compulsive grooming. Our data reveal that dietary zinc alters neurological function from synapses to behavior, and identifies dietary zinc as a potential therapeutic agent in ASD.
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Affiliation(s)
- Chantelle Fourie
- Department of Physiology and Centre for Brain Research, University of Auckland, Auckland, New Zealand
| | - Yukti Vyas
- Department of Physiology and Centre for Brain Research, University of Auckland, Auckland, New Zealand
| | - Kevin Lee
- Department of Physiology and Centre for Brain Research, University of Auckland, Auckland, New Zealand
| | - Yewon Jung
- Department of Physiology and Centre for Brain Research, University of Auckland, Auckland, New Zealand
| | - Craig C Garner
- German Center for Neurodegenerative Disorders, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johanna M Montgomery
- Department of Physiology and Centre for Brain Research, University of Auckland, Auckland, New Zealand
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39
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Moon AL, Haan N, Wilkinson LS, Thomas KL, Hall J. CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis. Schizophr Bull 2018; 44:958-965. [PMID: 29982775 PMCID: PMC6101623 DOI: 10.1093/schbul/sby096] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Large-scale genome-wide association studies have consistently shown that genetic variation in CACNA1C, a gene that encodes calcium voltage-gated channel subunit alpha1C, increases risk for psychiatric disorders. CACNA1C encodes the Cav1.2 subunit of voltage-gated calcium channels, which themselves have been functionally implicated in a broad spectrum of neuropsychiatric syndromes. Research has concentrated on uncovering the underlying biological mechanisms that could be responsible for this increased risk. This review presents an overview of recent findings regarding Cacna1c variation in animal models, particularly focusing on behavioral phenotypes associated with neurodevelopmental disorders such as cognition, anxiety and depressive phenotypes, and fear conditioning. The impact of reduced gene dosage of Cacna1c on adult hippocampal neurogenesis is also assessed, including new data from a novel Cacna1c+/- rat model.
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Affiliation(s)
- Anna L Moon
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - Niels Haan
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
| | - Lawrence S Wilkinson
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
- School of Psychology, Cardiff University, Cardiff, UK
| | - Kerrie L Thomas
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
- School of Biosciences, Cardiff University, Cardiff, UK
| | - Jeremy Hall
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
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40
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Kisko TM, Braun MD, Michels S, Witt SH, Rietschel M, Culmsee C, Schwarting RKW, Wöhr M. Cacna1c haploinsufficiency leads to pro-social 50-kHz ultrasonic communication deficits in rats. Dis Model Mech 2018; 11:dmm.034116. [PMID: 29739816 PMCID: PMC6031367 DOI: 10.1242/dmm.034116] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 04/27/2018] [Indexed: 12/12/2022] Open
Abstract
The cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder (BPD) and schizophrenia (SCZ), with deficits in social functioning being common for all major neuropsychiatric disorders. In the present study, we explored the role of Cacna1c in regulating disorder-relevant behavioral phenotypes, focusing on socio-affective communication after weaning during the critical developmental period of adolescence in rats. To this aim, we used a newly developed genetic Cacna1c rat model and applied a truly reciprocal approach for studying communication through ultrasonic vocalizations, including both sender and receiver. Our results show that a deletion of Cacna1c leads to deficits in social behavior and pro-social 50-kHz ultrasonic communication in rats. Reduced levels of 50-kHz ultrasonic vocalizations emitted during rough-and-tumble play may suggest that Cacna1c haploinsufficient rats derive less reward from playful social interactions. Besides the emission of fewer 50-kHz ultrasonic vocalizations in the sender, Cacna1c deletion reduced social approach behavior elicited by playback of 50-kHz ultrasonic vocalizations. This indicates that Cacna1c haploinsufficiency has detrimental effects on 50-kHz ultrasonic communication in both sender and receiver. Together, these data suggest that Cacna1c plays a prominent role in regulating socio-affective communication in rats with relevance for ASD, BPD and SCZ. This article has an associated First Person interview with the first author of the paper. Summary: The present study suggests that Cacna1c plays a prominent role in regulating socio-affective communication in rats with relevance for neuropsychiatric disorders.
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Affiliation(s)
- Theresa M Kisko
- Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenbergstr. 18, D-35032 Marburg, Germany
| | - Moria D Braun
- Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenbergstr. 18, D-35032 Marburg, Germany
| | - Susanne Michels
- Institute of Pharmacology and Clinical Pharmacy, Philipps-University of Marburg, Karl-von-Frisch-Str. 1, D-35032 Marburg, Germany
| | - Stephanie H Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, J5, D-65189 Mannheim, Germany
| | - Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Faculty of Medicine Mannheim, University of Heidelberg, J5, D-65189 Mannheim, Germany
| | - Carsten Culmsee
- Institute of Pharmacology and Clinical Pharmacy, Philipps-University of Marburg, Karl-von-Frisch-Str. 1, D-35032 Marburg, Germany.,Center for Mind, Brain, and Behavior (CMBB), Philipps-University of Marburg, Hans-Meerwein-Str. 6, D-35032 Marburg, Germany
| | - Rainer K W Schwarting
- Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenbergstr. 18, D-35032 Marburg, Germany.,Center for Mind, Brain, and Behavior (CMBB), Philipps-University of Marburg, Hans-Meerwein-Str. 6, D-35032 Marburg, Germany
| | - Markus Wöhr
- Behavioral Neuroscience, Experimental and Biological Psychology, Faculty of Psychology, Philipps-University of Marburg, Gutenbergstr. 18, D-35032 Marburg, Germany .,Center for Mind, Brain, and Behavior (CMBB), Philipps-University of Marburg, Hans-Meerwein-Str. 6, D-35032 Marburg, Germany
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41
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Modi ME, Brooks JM, Guilmette ER, Beyna M, Graf R, Reim D, Schmeisser MJ, Boeckers TM, O'Donnell P, Buhl DL. Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism. Front Mol Neurosci 2018; 11:107. [PMID: 29970986 PMCID: PMC6018399 DOI: 10.3389/fnmol.2018.00107] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 03/19/2018] [Indexed: 12/02/2022] Open
Abstract
Mutations in the SHANK family of genes have been consistently identified in genetic and genomic screens of autism spectrum disorder (ASD). The functional overlap of SHANK with several other ASD-associated genes suggests synaptic dysfunction as a convergent mechanism of pathophysiology in ASD. Although many ASD-related mutations result in alterations to synaptic function, the nature of those dysfunctions and the consequential behavioral manifestations are highly variable when expressed in genetic mouse models. To investigate the phylogenetic conservation of phenotypes resultant of Shank2 loss-of-function in a translationally relevant animal model, we generated and characterized a novel transgenic rat with a targeted mutation of the Shank2 gene, enabling an evaluation of gene-associated phenotypes, the elucidation of complex behavioral phenotypes, and the characterization of potential translational biomarkers. The Shank2 loss-of-function mutation resulted in a notable phenotype of hyperactivity encompassing hypermotivation, increased locomotion, and repetitive behaviors. Mutant rats also expressed deficits in social behavior throughout development and in the acquisition of operant tasks. The hyperactive phenotype was associated with an upregulation of mGluR1 expression, increased dendritic branching, and enhanced long-term depression (LTD) in the striatum but opposing morphological and cellular alterations in the hippocampus (HP). Administration of the mGluR1 antagonist JNJ16259685 selectively normalized the expression of striatally mediated repetitive behaviors and physiology but had no effect on social deficits. Finally, Shank2 mutant animals also exhibited alterations in electroencephalography (EEG) spectral power and event-related potentials, which may serve as translatable EEG biomarkers of synaptopathic alterations. Our results show a novel hypermotivation phenotype that is unique to the rat model of Shank2 dysfunction, in addition to the traditional hyperactive and repetitive behaviors observed in mouse models. The hypermotivated and hyperactive phenotype is associated with striatal dysfunction, which should be explored further as a targetable mechanism for impairment in ASD.
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Affiliation(s)
- Meera E Modi
- Pfizer Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States
| | - Julie M Brooks
- Pfizer Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States
| | - Edward R Guilmette
- Pfizer Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States
| | - Mercedes Beyna
- Pfizer Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States
| | - Radka Graf
- Pfizer Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States
| | - Dominik Reim
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
| | - Michael J Schmeisser
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.,Division of Neuroanatomy, Institute of Anatomy, Otto-von-Guericke University, Magdeburg, Germany.,Leibniz Institute for Neurobiology, Magdeburg, Germany
| | - Tobias M Boeckers
- Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany
| | - Patricio O'Donnell
- Pfizer Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States
| | - Derek L Buhl
- Pfizer Internal Medicine Research Unit, Pfizer Inc., Cambridge, MA, United States
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42
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Braun MD, Kisko TM, Vecchia DD, Andreatini R, Schwarting RKW, Wöhr M. Sex-specific effects of Cacna1c haploinsufficiency on object recognition, spatial memory, and reversal learning capabilities in rats. Neurobiol Learn Mem 2018; 155:543-555. [PMID: 29800644 DOI: 10.1016/j.nlm.2018.05.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/03/2018] [Accepted: 05/17/2018] [Indexed: 10/16/2022]
Abstract
The CACNA1C gene is strongly implicated in the etiology of multiple major neuropsychiatric disorders, such as bipolar disorder, major depression, and schizophrenia, with cognitive deficits being a common feature. It is unclear, however, by which mechanisms CACNA1C variants advance the risk of developing neuropsychiatric disorders. This study set out to investigate cognitive functioning in a newly developed genetic Cacna1c rat model. Specifically, spatial and reversal learning, as well as object recognition memory were assessed in heterozygous Cacna1c+/- rats and compared to wildtype Cacna1c+/+ littermate controls in both sexes. Our results show that both Cacna1c+/+ and Cacna1c+/- animals were able to learn the rewarded arm configuration of a radial maze over the course of seven days. Both groups also showed reversal learning patterns indicative of intact abilities. In females, genotype differences were evident in the initial spatial learning phase, with Cacna1c+/- females showing hypo-activity and fewer mixed errors. In males, a difference was found during probe trials for both learning phases, with Cacna1c+/- rats displaying better distinction between previously baited and non-baited arms; and regarding cognitive flexibility in favor of the Cacna1c+/+ animals. All experimental groups proved to be sensitive to reward magnitude and fully able to distinguish between novel and familiar objects in the novel object recognition task. Taken together, these results indicate that Cacna1c haploinsufficiency has a minor, but positive impact on (spatial) memory functions in rats.
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Affiliation(s)
- Moria D Braun
- Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany
| | - Theresa M Kisko
- Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany
| | - Débora Dalla Vecchia
- Laboratory of Physiology and Pharmacology of the Central Nervous System, Department of Pharmacology, Federal University of Paraná, Centro Politécnico, 81540-990 Curitiba, PR, Brazil
| | - Roberto Andreatini
- Laboratory of Physiology and Pharmacology of the Central Nervous System, Department of Pharmacology, Federal University of Paraná, Centro Politécnico, 81540-990 Curitiba, PR, Brazil
| | - Rainer K W Schwarting
- Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany; Center for Mind, Brain and Behavior, Philipps-University of Marburg, Hans-Meerwein-Str. 6, D-35032 Marburg, Germany
| | - Markus Wöhr
- Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Gutenberg-Str. 18, D-35032 Marburg, Germany; Center for Mind, Brain and Behavior, Philipps-University of Marburg, Hans-Meerwein-Str. 6, D-35032 Marburg, Germany.
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Berg EL, Copping NA, Rivera JK, Pride MC, Careaga M, Bauman MD, Berman RF, Lein PJ, Harony-Nicolas H, Buxbaum JD, Ellegood J, Lerch JP, Wöhr M, Silverman JL. Developmental social communication deficits in the Shank3 rat model of phelan-mcdermid syndrome and autism spectrum disorder. Autism Res 2018; 11:587-601. [PMID: 29377611 DOI: 10.1002/aur.1925] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 12/19/2017] [Accepted: 12/30/2017] [Indexed: 12/15/2022]
Abstract
Mutations in the SHANK3 gene have been discovered in autism spectrum disorder (ASD), and the intellectual disability, Phelan-McDermid Syndrome. This study leveraged a new rat model of Shank3 deficiency to assess complex behavioral phenomena, unique to rats, which display a richer social behavior repertoire than mice. Uniquely detectable emissions of ultrasonic vocalizations (USV) in rats serve as situation-dependent affective signals and accomplish important communicative functions. We report, for the first time, a call and response acoustic playback assay of bidirectional social communication in juvenile Shank3 rats. Interestingly, we found that Shank3-deficient null males did not demonstrate the enhanced social approach behavior typically exhibited following playback of pro-social USV. Concomitantly, we discovered that emission of USV in response to playback was not genotype-dependent and emitted response calls were divergent in meaning. This is the first report of these socially relevant responses using a genetic model of ASD. A comprehensive and empirical analysis of vigorous play during juvenile reciprocal social interactions further revealed fewer bouts and reduced durations of time spent playing by multiple key parameters, including reduced anogenital sniffing and allogrooming. We further discovered that male null Shank3-deficient pups emitted fewer isolation-induced USV than Shank3 wildtype controls. Postnatal whole brain anatomical phenotyping was applied to visualize anatomical substrates that underlie developmental phenotypes. The data presented here lend support for the important role of Shank3 in social communication, the core symptom domain of ASD. By increasing the number of in vivo functional outcome measures, we improved the likelihood for identifying and moving forward with medical interventions. Autism Res 2018, 11: 587-601. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY Clinically relevant outcomes are required to demonstrate the utility of therapeutics. We introduce findings in a rat model, and assess the impact of mutations in Shank3, an autism risk gene. We found that males with deficient expression of Shank3 did not demonstrate typical responses in a bi-directional social communication test and that social interaction was lower on key parameters. Outcome measures reported herein extend earlier results in mice and capture responses to acoustic calls, which is analogous to measuring receptive and expressive communication.
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Affiliation(s)
- Elizabeth L Berg
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
| | - Nycole A Copping
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
| | - Josef K Rivera
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
| | - Michael C Pride
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
| | - Milo Careaga
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
| | - Melissa D Bauman
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
| | - Robert F Berman
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
| | - Pamela J Lein
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
| | - Hala Harony-Nicolas
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Joseph D Buxbaum
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jacob Ellegood
- Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Canada
| | - Jason P Lerch
- Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Markus Wöhr
- Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Gutenbergstr. 18, Marburg, D-35032, Germany.,Marburg Center for Mind, Brain, and Behavior (MCMBB), Marburg, Germany
| | - Jill L Silverman
- University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA
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