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Noda M, Matsumoto A, Ito H, Kagami M, Tajima T, Matsumura T, Yamagata T, Nagata KI. An unstable variant of GAP43 leads to neurodevelopmental deficiency. Sci Rep 2024; 14:31911. [PMID: 39738362 PMCID: PMC11686380 DOI: 10.1038/s41598-024-83445-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 12/16/2024] [Indexed: 01/02/2025] Open
Abstract
Growth-associated protein 43 (GAP43) is a membrane-associated phosphoprotein predominantly expressed in the nervous systems, and controls axonal growth, branching, and pathfinding. While the association between GAP43 and human neurological disorders have been reported, the underlying mechanisms remain largely unknown. We performed whole exome sequencing on a patient with intellectual disability (ID), neurodevelopmental disorders, short stature, and skeletal abnormalities such as left-right difference in legs and digital deformities, and identified a heterozygous missense variation in the GAP43 gene [NM_001130064.2: c.436G > A/p.(E146K)]. The variant GAP43 protein was unstable in primary cultured cortical neurons and hippocampal neurons in vitro. In utero electroporation of the variant protein also confirmed its instability in vivo, suggesting that the variant led to a condition similar with haploinsufficiency in the patient. Silencing of GAP43 via in utero electroporation of RNAi vectors demonstrated that loss of GAP43 suppressed axon elongation into the contralateral hemisphere and impaired the dendritic arbor formation as shown by decreased dendritic branch points and shortened total dendritic lengths. Collectively, these findings confirmed the critical roles of GAP43 in brain development and the pathological basis of GAP43-associated diseases. Our study will contribute to a better understanding of how dysregulation of GAP43 leads to human diseases.
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Affiliation(s)
- Mariko Noda
- Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, Aichi, 480-0392, Japan
| | - Ayumi Matsumoto
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
- Division of Cardiovascular and Genetic Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 YakushijiShimotsuke-Shi, Tochigi-Ken, 329-0498, Japan
| | - Hidenori Ito
- Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, Aichi, 480-0392, Japan
| | - Masayo Kagami
- Clinical Endocrine Research Division, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Toshihiro Tajima
- Department of Pediatrics, Jichi Medical University, Tochigi, Japan
| | - Takayoshi Matsumura
- Division of Cardiovascular and Genetic Research, Center for Molecular Medicine, Jichi Medical University, 3311-1 YakushijiShimotsuke-Shi, Tochigi-Ken, 329-0498, Japan.
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University, Tochigi, Japan.
| | | | - Koh-Ichi Nagata
- Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, 713-8 Kamiya, Kasugai, Aichi, 480-0392, Japan.
- Department of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
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Maroto IB, Costas-Insua C, Montero-Fernández C, Hermoso-López A, Lebouc M, Bajo-Grañeras R, Álvaro-Blázquez A, Blázquez C, Cannich A, Marsicano G, Martín R, Baufreton J, Rodríguez-Crespo I, Bellocchio L, Guzmán M. GAP43 Located on Corticostriatal Terminals Restrains Novelty-Induced Hyperactivity in Mice. J Neurosci 2024; 44:e0701242024. [PMID: 39168654 PMCID: PMC11426381 DOI: 10.1523/jneurosci.0701-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/10/2024] [Accepted: 07/31/2024] [Indexed: 08/23/2024] Open
Abstract
Growth-associated protein of 43 kDa (GAP43) is a key cytoskeleton-associated component of the presynaptic terminal that facilitates neuroplasticity. Downregulation of GAP43 expression has been associated to various psychiatric conditions in humans and evokes hippocampus-dependent memory impairments in mice. Despite the extensive studies conducted on hippocampal GAP43 in past decades, however, very little is known about its roles in modulating the excitatory versus inhibitory balance in other brain regions. We recently generated conditional knock-out mice in which the Gap43 gene was selectively inactivated in either telencephalic glutamatergic neurons (Gap43fl/fl ;Nex1Cre mice, hereafter Glu-GAP43-/- mice) or forebrain GABAergic neurons (Gap43fl/fl ;Dlx5/6Cre mice, hereafter GABA-GAP43-/- mice). Here, we show that Glu-GAP43-/- but not GABA-GAP43-/- mice of either sex show a striking hyperactive phenotype when exposed to a novel environment. This behavioral alteration of Glu-GAP43-/- mice was linked to a selective activation of dorsal-striatum neurons, as well as to an enhanced corticostriatal glutamatergic transmission and an abrogation of corticostriatal endocannabinoid-mediated long-term depression. In line with these observations, GAP43 was abundantly expressed in corticostriatal glutamatergic terminals of wild-type mice. The novelty-induced hyperactive phenotype of Glu-GAP43-/- mice was abrogated by chemogenetically inhibiting corticostriatal afferences with a Gi-coupled "designer receptor exclusively activated by designer drugs" (DREADDs), thus further supporting that novelty-induced activity is controlled by GAP43 at corticostriatal excitatory projections. Taken together, these findings show an unprecedented regulatory role of GAP43 in the corticostriatal circuitry and provide a new mouse model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity, a phenotypic shortfall that occurs in diverse psychiatric diseases.
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Affiliation(s)
- Irene B Maroto
- Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid ES-28029, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid ES-28034, Spain
| | - Carlos Costas-Insua
- Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid ES-28029, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid ES-28034, Spain
| | - Carlos Montero-Fernández
- Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid ES-28029, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid ES-28034, Spain
| | - Alba Hermoso-López
- Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid ES-28029, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid ES-28034, Spain
| | - Margaux Lebouc
- University of Bordeaux, CNRS, IMN, UMR 5293, Bordeaux F-33000, France
| | - Raquel Bajo-Grañeras
- Department of Physiology, School of Medicine, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
| | - Alicia Álvaro-Blázquez
- Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid ES-28029, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid ES-28034, Spain
| | - Cristina Blázquez
- Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid ES-28029, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid ES-28034, Spain
| | - Astrid Cannich
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux F-33000, France
| | - Giovanni Marsicano
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux F-33000, France
| | - Ricardo Martín
- Department of Physiology, School of Medicine, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
| | - Jérôme Baufreton
- University of Bordeaux, CNRS, IMN, UMR 5293, Bordeaux F-33000, France
| | - Ignacio Rodríguez-Crespo
- Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid ES-28029, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid ES-28034, Spain
| | - Luigi Bellocchio
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux F-33000, France
| | - Manuel Guzmán
- Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid ES-28029, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid ES-28034, Spain
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Wu XL, Yan QJ, Zhu F. Abnormal synaptic plasticity and impaired cognition in schizophrenia. World J Psychiatry 2022; 12:541-557. [PMID: 35582335 PMCID: PMC9048451 DOI: 10.5498/wjp.v12.i4.541] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/28/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Schizophrenia (SCZ) is a severe mental illness that affects several brain domains with relation to cognition and behaviour. SCZ symptoms are typically classified into three categories, namely, positive, negative, and cognitive. The etiology of SCZ is thought to be multifactorial and poorly understood. Accumulating evidence has indicated abnormal synaptic plasticity and cognitive impairments in SCZ. Synaptic plasticity is thought to be induced at appropriate synapses during memory formation and has a critical role in the cognitive symptoms of SCZ. Many factors, including synaptic structure changes, aberrant expression of plasticity-related genes, and abnormal synaptic transmission, may influence synaptic plasticity and play vital roles in SCZ. In this article, we briefly summarize the morphology of the synapse, the neurobiology of synaptic plasticity, and the role of synaptic plasticity, and review potential mechanisms underlying abnormal synaptic plasticity in SCZ. These abnormalities involve dendritic spines, postsynaptic density, and long-term potentiation-like plasticity. We also focus on cognitive dysfunction, which reflects impaired connectivity in SCZ. Additionally, the potential targets for the treatment of SCZ are discussed in this article. Therefore, understanding abnormal synaptic plasticity and impaired cognition in SCZ has an essential role in drug therapy.
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Affiliation(s)
- Xiu-Lin Wu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Qiu-Jin Yan
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan 430071, Hubei Province, China
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Grijalva LE, Miranda MI, Paredes RG. Differential changes in GAP-43 or synaptophysin during appetitive and aversive taste memory formation. Behav Brain Res 2020; 397:112937. [PMID: 32991926 DOI: 10.1016/j.bbr.2020.112937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 09/19/2020] [Accepted: 09/21/2020] [Indexed: 10/23/2022]
Abstract
Association between events in time and space is a major mechanism for all animals, including humans, which allows them to learn about the world and potentially change their behavior in the future to adapt to different environments. Conditioning taste aversion (CTA) is a single-trial learning paradigm where animals are trained to avoid a novel flavor which is associated with malaise. Many variables can be analyzed with this model and the circuits involved are well described. Thus, the amygdala and the gustatory cortex (GC) are some of the most relevant structures involved in CTA. In the present study we focused in plastic changes that occur during appetitive and/or aversive taste memory formation. Previous studies have demonstrated that memory consolidation, in hippocampal dependent paradigms, induces plastic changes like increase in the concentration of proteins considered as markers of neuronal plasticity, such as the growth associated protein 43 (GAP-43) and synaptophysin (SYN). In the present experiment in male rats we evaluated changes in GAP-43 and SYN expression, using immunofluorescence, induce by the formation of aversive and appetitive taste memory. We found that taste aversive memory formation can induce an increase in GAP-43 in the granular layer of the GC. Furthermore, we also found an increase in SYN expression in both layers of the GC, the basolateral amygdala (BLA) and the central amygdala (CeA). These results suggest that aversive memory representation induces a new circuitry (inferred from an increase in GAP 43). On the other hand, an appetitive taste learning increased SYN expression in the GC (both layers), the BLA and the CeA without any changes in GAP 43. Together these results indicate that aversive memory formation induces structural and synaptic changes, while appetitive memory formation induces synaptic changes; suggesting that aversive and appetitive memories require a different set of cortical and amygdala plastic changes.
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Affiliation(s)
- Lucia E Grijalva
- Instituto de Neurobiología, UNAM, Campus Juriquilla, Querétaro, 76230, Mexico
| | - María I Miranda
- Instituto de Neurobiología, UNAM, Campus Juriquilla, Querétaro, 76230, Mexico
| | - Raúl G Paredes
- Instituto de Neurobiología, UNAM, Campus Juriquilla, Querétaro, 76230, Mexico; Escuela Nacional de Estudios Superiores, Unidad Juriquilla, UNAM, Querétaro, 76230 Mexico.
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Bobilev AM, Perez JM, Tamminga CA. Molecular alterations in the medial temporal lobe in schizophrenia. Schizophr Res 2020; 217:71-85. [PMID: 31227207 DOI: 10.1016/j.schres.2019.06.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/29/2019] [Accepted: 06/01/2019] [Indexed: 11/30/2022]
Abstract
The medial temporal lobe (MTL) and its individual structures have been extensively implicated in schizophrenia pathophysiology, with considerable efforts aimed at identifying structural and functional differences in this brain region. The major structures of the MTL for which prominent differences have been revealed include the hippocampus, the amygdala and the superior temporal gyrus (STG). The different functions of each of these regions have been comprehensively characterized, and likely contribute differently to schizophrenia. While neuroimaging studies provide an essential framework for understanding the role of these MTL structures in various aspects of the disease, ongoing efforts have sought to employ molecular measurements in order to elucidate the biology underlying these macroscopic differences. This review provides a summary of the molecular findings in three major MTL structures, and discusses convergent findings in cellular architecture and inter-and intra-cellular networks. The findings of this effort have uncovered cell-type, network and gene-level specificity largely unique to each brain region, indicating distinct molecular origins of disease etiology. Future studies should test the functional implications of these molecular changes at the circuit level, and leverage new advances in sequencing technology to further refine our understanding of the differential contribution of MTL structures to schizophrenia.
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Affiliation(s)
- Anastasia M Bobilev
- Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, United States of America.
| | - Jessica M Perez
- Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, United States of America.
| | - Carol A Tamminga
- Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX, United States of America.
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Pinner AL, Mueller TM, Alganem K, McCullumsmith R, Meador-Woodruff JH. Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex. Transl Psychiatry 2020; 10:3. [PMID: 32066669 PMCID: PMC7026430 DOI: 10.1038/s41398-019-0610-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 09/09/2019] [Accepted: 10/03/2019] [Indexed: 12/22/2022] Open
Abstract
The pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein-protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated posttranslational lipid modifications may play a role in multiple neuropsychiatric disorders, including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of S-palmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that, in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (n = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine whether upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1 and prenylation-dependent processing enzymes RCE and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B, and RABGGTB in the cortex from rats treated long-term with haloperidol decanoate and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein-protein interactions and protein localization in schizophrenia.
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Affiliation(s)
- Anita L Pinner
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294-0021, USA.
| | - Toni M Mueller
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294-0021, USA
| | - Khaled Alganem
- Department of Neurosciences, University of Toledo, Toledo, OH, 43614-2598, USA
| | | | - James H Meador-Woodruff
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294-0021, USA
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Zak N, Moberget T, Bøen E, Boye B, Waage TR, Dietrichs E, Harkestad N, Malt UF, Westlye LT, Andreassen OA, Andersson S, Elvsåshagen T. Longitudinal and cross-sectional investigations of long-term potentiation-like cortical plasticity in bipolar disorder type II and healthy individuals. Transl Psychiatry 2018; 8:103. [PMID: 29795193 PMCID: PMC5966393 DOI: 10.1038/s41398-018-0151-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 01/19/2018] [Accepted: 03/26/2018] [Indexed: 12/12/2022] Open
Abstract
Visual evoked potential (VEP) plasticity is a promising assay for noninvasive examination of long-term potentiation (LTP)-like synaptic processes in the cerebral cortex. We conducted longitudinal and cross-sectional investigations of VEP plasticity in controls and individuals with bipolar disorder (BD) type II. VEP plasticity was assessed at baseline, as described previously (Elvsåshagen et al. Biol Psychiatry 2012), and 2.2 years later, at follow-up. The longitudinal sample with VEP data from both time points comprised 29 controls and 16 patients. VEP data were available from 13 additional patients at follow-up (total n = 58). VEPs were evoked by checkerboard reversals in two premodulation blocks before and six blocks after a plasticity-inducing block of prolonged (10 min) visual stimulation. VEP plasticity was computed by subtracting premodulation VEP amplitudes from postmodulation amplitudes. Saliva samples for cortisol analysis were collected immediately after awakening in the morning, 30 min later, and at 12:30 PM, at follow-up. We found reduced VEP plasticity in BD type II, that impaired plasticity was present in the euthymic phases of the illness, and that VEP plasticity correlated negatively with depression severity. There was a positive association between VEP plasticity and saliva cortisol in controls, possibly reflecting an inverted U-shaped relationship between cortisol and synaptic plasticity. VEP plasticity exhibited moderate temporal stability over a period of 2.2 years. The present study provides additional evidence for impaired LTP-like cortical plasticity in BD type II. VEP plasticity is an accessible method, which may help elucidate the pathophysiological and clinical significance of synaptic dysfunction in psychiatric disorders.
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Affiliation(s)
- Nathalia Zak
- 0000 0004 0389 8485grid.55325.34Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway ,0000 0004 1936 8921grid.5510.1Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Torgeir Moberget
- 0000 0004 0389 8485grid.55325.34Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway
| | - Erlend Bøen
- 0000 0004 0512 8628grid.413684.cDepartment of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway
| | - Birgitte Boye
- 0000 0004 0389 8485grid.55325.34Section of Psychosocial Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway ,0000 0004 1936 8921grid.5510.1Department of Behavioural Sciences in Medicine, University of Oslo, Oslo, Norway
| | - Trine R. Waage
- 0000 0004 1936 8921grid.5510.1Department of Psychology, University of Oslo, Oslo, Norway
| | - Espen Dietrichs
- 0000 0004 1936 8921grid.5510.1Institute of Clinical Medicine, University of Oslo, Oslo, Norway ,0000 0004 0389 8485grid.55325.34Department of Neurology, Oslo University Hospital, Oslo, Norway
| | - Nina Harkestad
- 0000 0004 1936 7443grid.7914.bDepartment of Biological and Medical Pscyhology, University of Bergen, Bergen, Norway
| | - Ulrik F. Malt
- 0000 0004 1936 8921grid.5510.1Institute of Clinical Medicine, University of Oslo, Oslo, Norway ,0000 0004 0389 8485grid.55325.34Department of Research and Education, Oslo University Hospital, Oslo, Norway
| | - Lars T. Westlye
- 0000 0004 0389 8485grid.55325.34Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway ,0000 0004 1936 8921grid.5510.1Department of Psychology, University of Oslo, Oslo, Norway
| | - Ole A. Andreassen
- 0000 0004 0389 8485grid.55325.34Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway ,0000 0004 1936 8921grid.5510.1Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Stein Andersson
- 0000 0004 1936 8921grid.5510.1Department of Psychology, University of Oslo, Oslo, Norway
| | - Torbjørn Elvsåshagen
- Norwegian Centre for Mental Disorders Research (NORMENT), KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway. .,Department of Neurology, Oslo University Hospital, Oslo, Norway.
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Evaluation of the Role of ABCB1gene Polymorphic Variants on Psychiatric Disorders Predisposition in Macedonian Population. ACTA ACUST UNITED AC 2017; 38:71-88. [PMID: 29668471 DOI: 10.2478/prilozi-2018-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The psychiatric and other CNS disorders are characterized with unregulated neuro-inflammatory processes and chronic microglia cell activation resulting with detrimental effect. ABCB1gene polymorphismsC1236T, G2677T/Aand C3435T are associated with P-glycoprotein expression and function andare linked with predisposition to psychiatric disorders such as schizophrenia and bipolar disorders. The relationship between mood disorders and glucocorticoids has been confirmed and ABCB1 SNPs influence the glucocorticoids access to the brain. The aim of the study is evaluation of the influence of the three most common ABCB1SNPs on predisposition to psychiatric disorders in Macedonian population. In the study 107 unrelated healthy Macedonians of both sexes were enrolled as a control group and patient population of 54 patients (22 to 65 years old) diagnosed with schizophrenia or bipolar disorder. ABCB1 for three polymorphisms were analyzed by Real-Time PCR in both groups. The results have confirmed the role of the ABCB1 gene in predisposition to psychiatric disorders and increased risk of developing bipolar disorder in carriers of the heterozygotes and mutant homozygotes for polymorphic variations in 1236 and 2677 in comparison to the normal genotype carriers. Three-fold higher risk was estimated for psychiatric illness in women that are 1236 and 2677 heterozygous carrier (heterozygous and mutant homozygous) compared to healthy control (men and women) population and four-fold higher risk in comparison only to healthy women population. Mutant allele carriers for 1236 and 2677 polymorphisms that are 35 years and below in patients population have almost three-fold higher risk for development of psychiatric illness.
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Saxena A, Scaini G, Bavaresco DV, Leite C, Valvassori SS, Carvalho AF, Quevedo J. Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature. MOLECULAR NEUROPSYCHIATRY 2017; 3:108-124. [PMID: 29230399 DOI: 10.1159/000480349] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 08/14/2017] [Indexed: 12/19/2022]
Abstract
Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.
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Affiliation(s)
- Ashwini Saxena
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Giselli Scaini
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Daniela V Bavaresco
- Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
| | - Camila Leite
- Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
| | - Samira S Valvassori
- Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil
| | - André F Carvalho
- Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceara, Fortaleza, Brazil
| | - João Quevedo
- Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.,Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, Brazil.,Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.,Neuroscience Graduate Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA
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10
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Rymo I, Kern S, Bjerke M, Zetterberg H, Marlow T, Blennow K, Gudmundsson P, Skoog I, Waern M. CSF YKL-40 and GAP-43 are related to suicidal ideation in older women. Acta Psychiatr Scand 2017; 135:351-357. [PMID: 28211584 DOI: 10.1111/acps.12701] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/09/2017] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To investigate possible relationships between suicidal ideation and cerebrospinal fluid (CSF) levels of glial markers YKL-40 (also known as chitinase-3-like protein 1), growth-associated protein-43 (GAP-43) and myelin basic protein (MBP). METHOD The sample was obtained from the Prospective Population Study of Women and included 86 women without dementia who underwent both psychiatric examinations and lumbar puncture (LP). Eight of these women reported past-month suicidal ideation. RESULTS Significantly, higher CSF levels of both YKL-40 and GAP-43 were detected in women with past-month suicidal ideation. Associations with suicidal ideation remained for both YKL-40 and GAP-43 in regression models adjusted for smoking status, BMI and age. CSF levels of YKL-40, GAP-43 and MBP did not differ by depression status. Higher levels of CSF GAP-43 were associated with feelings of worthlessness; a strong relationship was demonstrated in the fully adjusted model (OR 5.95 CI [1.52-23.20], P = 0.01). CONCLUSION Our findings of elevated CSF concentrations of both YKL-40 and GAP-43 in women with suicidal ideation, compared to those without, suggest that a disrupted synaptic glial functioning and inflammation may be related to the aetiology of suicidal ideation in older adults.
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Affiliation(s)
- I Rymo
- Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - S Kern
- Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - M Bjerke
- Reference Center for Biological Markers of Dementia, Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | - H Zetterberg
- Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.,UCL Institute of Neurology, Queen Square, London, UK
| | - T Marlow
- Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - K Blennow
- Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - P Gudmundsson
- Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - I Skoog
- Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - M Waern
- Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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11
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Williams KR, McAninch DS, Stefanovic S, Xing L, Allen M, Li W, Feng Y, Mihailescu MR, Bassell GJ. hnRNP-Q1 represses nascent axon growth in cortical neurons by inhibiting Gap-43 mRNA translation. Mol Biol Cell 2015; 27:518-34. [PMID: 26658614 PMCID: PMC4751602 DOI: 10.1091/mbc.e15-07-0504] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 12/01/2015] [Indexed: 11/11/2022] Open
Abstract
A novel posttranscriptional mechanism for regulating the neuronal protein GAP-43 is reported. The mRNA-binding protein hnRNP-Q1 represses Gap-43 mRNA translation by a mechanism involving a 5′ untranslated region G-quadruplex structure, which affects GAP-43 function, as demonstrated by a GAP-43–dependent increase in neurite length and number with hnRNP-Q1 knockdown. Posttranscriptional regulation of gene expression by mRNA-binding proteins is critical for neuronal development and function. hnRNP-Q1 is an mRNA-binding protein that regulates mRNA processing events, including translational repression. hnRNP-Q1 is highly expressed in brain tissue, suggesting a function in regulating genes critical for neuronal development. In this study, we have identified Growth-associated protein 43 (Gap-43) mRNA as a novel target of hnRNP-Q1 and have demonstrated that hnRNP-Q1 represses Gap-43 mRNA translation and consequently GAP-43 function. GAP-43 is a neuronal protein that regulates actin dynamics in growth cones and facilitates axonal growth. Previous studies have identified factors that regulate Gap-43 mRNA stability and localization, but it remains unclear whether Gap-43 mRNA translation is also regulated. Our results reveal that hnRNP-Q1 knockdown increased nascent axon length, total neurite length, and neurite number in mouse embryonic cortical neurons and enhanced Neuro2a cell process extension; these phenotypes were rescued by GAP-43 knockdown. Additionally, we have identified a G-quadruplex structure in the 5′ untranslated region of Gap-43 mRNA that directly interacts with hnRNP-Q1 as a means to inhibit Gap-43 mRNA translation. Therefore hnRNP-Q1–mediated repression of Gap-43 mRNA translation provides an additional mechanism for regulating GAP-43 expression and function and may be critical for neuronal development.
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Affiliation(s)
- Kathryn R Williams
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322
| | - Damian S McAninch
- Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282
| | - Snezana Stefanovic
- Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282
| | - Lei Xing
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322
| | - Megan Allen
- Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322
| | - Wenqi Li
- Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322
| | - Yue Feng
- Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322
| | | | - Gary J Bassell
- Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322
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12
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Wolff AR, Bilkey DK. Prenatal immune activation alters hippocampal place cell firing characteristics in adult animals. Brain Behav Immun 2015; 48:232-43. [PMID: 25843370 DOI: 10.1016/j.bbi.2015.03.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Revised: 03/12/2015] [Accepted: 03/24/2015] [Indexed: 12/27/2022] Open
Abstract
Prenatal maternal immune activation (MIA) is a risk factor for several developmental neuropsychiatric disorders, including autism, bipolar disorder and schizophrenia. Adults with these disorders display alterations in memory function that may result from changes in the structure and function of the hippocampus. In the present study we use an animal model to investigate the effect that a transient prenatal maternal immune activation episode has on the spatially-modulated firing activity of hippocampal neurons in adult animals. MIA was induced in pregnant rat dams with a single injection of the synthetic cytokine inducer polyinosinic:polycytidylic acid (poly I:C) on gestational day 15. Control dams were given a saline equivalent. Firing activity and local field potentials (LFPs) were recorded from the CA1 region of the adult male offspring of these dams as they moved freely in an open arena. Most neurons displayed characteristic spatially-modulated 'place cell' firing activity and while there was no between-group difference in mean firing rate between groups, place cells had smaller place fields in MIA-exposed animals when compared to control-group cells. Cells recorded in MIA-group animals also displayed an altered firing-phase synchrony relationship to simultaneously recorded LFPs. When the floor of the arena was rotated, the place fields of MIA-group cells were more likely to shift in the same direction as the floor rotation, suggesting that local cues may have been more salient for these animals. In contrast, place fields in control group cells were more likely to shift firing position to novel spatial locations suggesting an altered response to contextual cues. These findings show that a single MIA intervention is sufficient to change several important characteristics of hippocampal place cell activity in adult offspring. These changes could contribute to the memory dysfunction that is associated with MIA, by altering the encoding of spatial context and by disrupting plasticity mechanisms that are dependent on spike timing synchrony.
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Affiliation(s)
- Amy R Wolff
- Department of Psychology, Brain Health Research Centre, University of Otago, Dunedin, New Zealand
| | - David K Bilkey
- Department of Psychology, Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
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13
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Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder? Neural Plast 2015; 2015:708306. [PMID: 26075104 PMCID: PMC4444594 DOI: 10.1155/2015/708306] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 02/02/2015] [Accepted: 02/05/2015] [Indexed: 01/01/2023] Open
Abstract
The blood-brain barrier (BBB) regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS) in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer's disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD), here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species) substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.
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14
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Kudryashova IV. Neurodegenerative changes in depression: Excitotoxicity or a deficit of trophic factors? NEUROCHEM J+ 2015. [DOI: 10.1134/s1819712415010043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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15
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Haarman BCMB, Riemersma-Van der Lek RF, de Groot JC, Ruhé HGE, Klein HC, Zandstra TE, Burger H, Schoevers RA, de Vries EFJ, Drexhage HA, Nolen WA, Doorduin J. Neuroinflammation in bipolar disorder - A [(11)C]-(R)-PK11195 positron emission tomography study. Brain Behav Immun 2014; 40:219-25. [PMID: 24703991 DOI: 10.1016/j.bbi.2014.03.016] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/11/2014] [Accepted: 03/23/2014] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND The "monocyte-T-cell theory of mood disorders" regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [(11)C]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential focus of neuroinflammation in bipolar disorder. We aim to determine if there is increased [(11)C]-(R)-PK11195 binding to activated microglia in the hippocampus of patients with bipolar I disorder when compared to healthy controls. MATERIAL AND METHODS Fourteen patients with bipolar I disorder and eleven healthy controls were included in the analyses. Dynamic 60-min PET scans were acquired after the injection of [(11)C]-(R)-PK11195. All subjects underwent psychiatric interviews as well as an MRI scan, which was used for anatomic co-registration in the data analysis. The data from the PET scans was analyzed with a two-tissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma and blood curve as input. RESULTS A significantly increased [(11)C]-(R)-PK11195 binding potential, which is indicative of neuroinflammation, was found in the right hippocampus of the patients when compared to the healthy controls (1.66 (CI 1.45-1.91) versus 1.33 (CI 1.16-1.53); p=0.033, respectively). Although the same trend was observed in the left hippocampus, this difference was not statistically significant. CONCLUSION This study is the first to demonstrate the presence of focal neuroinflammation in the right hippocampus in bipolar I disorder.
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Affiliation(s)
| | - Rixt F Riemersma-Van der Lek
- University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands
| | - Jan Cees de Groot
- University of Groningen, University Medical Center Groningen, Department of Radiology, Groningen, The Netherlands
| | - Henricus G Eric Ruhé
- University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands
| | - Hans C Klein
- University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands
| | - Tjitske E Zandstra
- University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands
| | - Huibert Burger
- University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of General Practice, Groningen, The Netherlands
| | - Robert A Schoevers
- University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands
| | - Erik F J de Vries
- University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands
| | - Hemmo A Drexhage
- Erasmus MC, Department of Immunology, Rotterdam, The Netherlands
| | - Willem A Nolen
- University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands
| | - Janine Doorduin
- University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands
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16
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Sinclair D, Fullerton JM, Webster MJ, Shannon Weickert C. Glucocorticoid receptor 1B and 1C mRNA transcript alterations in schizophrenia and bipolar disorder, and their possible regulation by GR gene variants. PLoS One 2012; 7:e31720. [PMID: 22427805 PMCID: PMC3302776 DOI: 10.1371/journal.pone.0031720] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2011] [Accepted: 01/18/2012] [Indexed: 01/01/2023] Open
Abstract
Abnormal patterns of HPA axis activation, under basal conditions and in response to stress, are found in individuals with schizophrenia and bipolar disorder. Altered glucocorticoid receptor (GR) mRNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) in psychiatric illness have also been reported, but the cause of these abnormalities is not known. We quantified expression of GR mRNA transcript variants which employ different 5′ promoters, in 35 schizophrenia cases, 31 bipolar disorder cases and 34 controls. We also explored whether sequence variation within the NR3C1 (GR) gene is related to GR mRNA variant expression. Total GR mRNA was decreased in the DLPFC in schizophrenia cases relative to controls (15.1%, p<0.0005) and also relative to bipolar disorder cases (8.9%, p<0.05). GR-1B mRNA was decreased in schizophrenia cases relative to controls (20.2%, p<0.05), while GR-1C mRNA was decreased in both schizophrenia and bipolar disorder cases relative to controls (16.1% and 17.2% respectively, both p<0.005). A dose-dependent effect of rs10052957 genotype on GR-1B mRNA expression was observed, where CC homozygotes displayed 18.4% lower expression than TC heterozygotes (p<0.05), and 31.8% lower expression than TT homozygotes (p<0.005). Similarly, a relationship between rs6190 (R23K) genotype and GR-1C expression was seen, with 24.8% lower expression in GG homozygotes than GA heterozygotes (p<0.01). We also observed an effect of rs41423247 (Bcl1) SNP on expression of 67 kDa GRα isoform, the most abundant GRα isoform in the DLPFC. These findings suggest possible roles for the GR-1B and GR-1C promoter regions in mediating GR gene expression changes in psychotic illness, and highlight the potential importance of sequence variation within the NR3C1 gene in modulating GR mRNA expression in the DLPFC.
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Affiliation(s)
- Duncan Sinclair
- Schizophrenia Research Institute, Sydney, New South Wales, Australia.
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17
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Evidence for impaired neocortical synaptic plasticity in bipolar II disorder. Biol Psychiatry 2012; 71:68-74. [PMID: 22036034 DOI: 10.1016/j.biopsych.2011.09.026] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2011] [Revised: 09/02/2011] [Accepted: 09/26/2011] [Indexed: 02/02/2023]
Abstract
BACKGROUND Synaptic plasticity might play an important role in the pathophysiology and treatment of bipolar disorders. There is, however, a paucity of human evidence supporting this hypothesis, mainly due to a lack of methods for noninvasive assessment of synaptic plasticity. It has recently been demonstrated that plasticity of the visual evoked potential (VEP) induced by repeated visual stimulation might reflect synaptic plasticity. In this study, we examined VEP plasticity in healthy control subjects and patients with bipolar II disorder (BD-II). METHODS Forty healthy control subjects and 26 individuals with a DSM-IV diagnosis of BD-II matched for age and gender participated. The VEPs were evoked by checkerboard reversal stimulation before and after a modulation block of prolonged (10 min) visual stimulation. RESULTS The modulation block resulted in significant VEP plasticity in healthy control subjects. The VEP plasticity was significantly impaired in patients with BD-II. Explorative analyses indicated a trend toward a less severe impairment in medicated than in unmedicated patients. CONCLUSIONS Visual evoked potential plasticity might represent a reliable and robust assay for studies of synaptic plasticity in vivo in humans. In addition, our findings support the hypothesis of impaired synaptic plasticity in BD-II. Longitudinal studies are needed to fully clarify the effects of medication and mood state on VEP plasticity.
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18
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Yamada K, Iwayama Y, Hattori E, Iwamoto K, Toyota T, Ohnishi T, Ohba H, Maekawa M, Kato T, Yoshikawa T. Genome-wide association study of schizophrenia in Japanese population. PLoS One 2011; 6:e20468. [PMID: 21674006 PMCID: PMC3108953 DOI: 10.1371/journal.pone.0020468] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Accepted: 04/26/2011] [Indexed: 12/04/2022] Open
Abstract
Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology.
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Affiliation(s)
- Kazuo Yamada
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
| | - Yoshimi Iwayama
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
| | - Eiji Hattori
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
| | - Kazuya Iwamoto
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan
| | - Tomoko Toyota
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
| | - Tetsuo Ohnishi
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
| | - Hisako Ohba
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
| | - Motoko Maekawa
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
| | - Tadafumi Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan
| | - Takeo Yoshikawa
- Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan
- * E-mail:
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19
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Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development. Mol Psychiatry 2011; 16:504-15. [PMID: 20308989 DOI: 10.1038/mp.2010.28] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The glucocorticoid receptor (GR) has a critical role in determining the brain's capacity to respond to stress, and has been implicated in the pathogenesis of psychiatric illness. We hypothesized that key changes in cortical GR occur during adolescence and young adulthood, at a time when individuals are at increased risk of developing schizophrenia, bipolar disorder and major depression. We investigated the mRNA and protein expression of GR in the dorsolateral prefrontal cortex across seven developmental time points from infancy to adulthood. GR mRNA expression, determined by microarray and quantitative real-time PCR, was lowest in neonates and peaked around young adulthood. Western blotting revealed two dynamic patterns of GRα protein expression across the lifespan, with N-terminal variants displaying differing unique patterns of abundance. GRα-A and a 67-kDa GRα isoform mirrored mRNA trends and peaked in toddlers and late in adolescence, whereas a 40-kDa isoform, very likely a GRα-D variant, peaked in neonates and decreased across the lifespan. GRα protein was localized to pyramidal neurons throughout life and most strikingly in young adulthood, but to white matter astrocytes only in neonates and infants (<130 days). These results suggest that the neonatal and late adolescent periods represent critical windows of stress pathway development, and highlight the importance of white matter astrocytes and pyramidal neurons, respectively, at these stages of cortical development. Evidence of dynamic patterns of GR isoform expression and cellular localization across development strengthens the hypothesis that windows of vulnerability to stress exist across human cortical development.
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20
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Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 2011; 14:123-30. [PMID: 20633320 DOI: 10.1017/s1461145710000805] [Citation(s) in RCA: 430] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical scavenger in the brain. Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. The aim of this study was to determine if mood disorders and SCZ are associated with abnormal GSH and its functionally related enzymes. Post-mortem prefrontal cortex from patients with BD, MDD, SCZ, and from non-psychiatric comparison controls were provided by the Stanley Foundation Neuropathology Consortium. Spectrophotometric analysis was utilized for the quantitative determination of GSH, while immunoblotting analyses were used to examine expression of glutamyl-cysteine ligase (GCL), GSH reductase (GR), and GSH peroxidase (GPx). We found that the levels of reduced, oxidized, and total GSH were significantly decreased in all psychiatric conditions compared to the control group. Although GCL and GR levels did not differ between groups, the levels of GPx were reduced in MDD and SCZ compared to control subjects. Since oxidative damage has been demonstrated in MDD, BD, and SCZ, our finding that GSH levels are reduced in post-mortem prefrontal cortex suggests that these patient groups may be more susceptible to oxidative stress.
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21
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Fung SJ, Sivagnanasundaram S, Shannon Weickert C. Lack of change in markers of presynaptic terminal abundance alongside subtle reductions in markers of presynaptic terminal plasticity in prefrontal cortex of schizophrenia patients. Biol Psychiatry 2011; 69:71-9. [PMID: 21145444 PMCID: PMC3001685 DOI: 10.1016/j.biopsych.2010.09.036] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2010] [Revised: 09/14/2010] [Accepted: 09/16/2010] [Indexed: 11/27/2022]
Abstract
BACKGROUND Reduced synaptic connectivity in frontal cortex may contribute to schizophrenia symptoms. While altered messenger RNA (mRNA) and protein expression of various synaptic genes have been found, discrepancies between studies mean a generalizable synaptic pathology has not been identified. METHODS We determined if mRNAs encoding presynaptic proteins enriched in inhibitory (vesicular gamma-aminobutyric acid transporter [VGAT] and complexin 1) and/or excitatory (vesicular glutamate transporter 1 [VGluT1] and complexin 2) terminals are altered in the dorsolateral prefrontal cortex of subjects with schizophrenia (n = 37 patients, n = 37 control subjects). We also measured mRNA expression of markers associated with synaptic plasticity/neurite outgrowth (growth associated protein 43 [GAP43] and neuronal navigators [NAVs] 1 and 2) and mRNAs of other synaptic-associated proteins previously implicated in schizophrenia: dysbindin and vesicle-associated membrane protein 1 (VAMP1) mRNAs using quantitative polymerase chain reaction. RESULTS No significant changes in complexin 1, VGAT, complexin 2, VGluT1, dysbindin, NAV2, or VAMP1 mRNA expression were found; however, expression of mRNAs associated with plasticity/cytoskeletal modification (GAP43 and NAV1) was reduced in schizophrenia. Although dysbindin mRNA did not differ in schizophrenia compared with control subjects, dysbindin mRNA positively correlated with GAP43 and NAV1 in schizophrenia but not in control subjects, suggesting low levels of dysbindin may be linked to reduced plasticity in the disease state. No relationships between three dysbindin genetic polymorphisms previously associated with dysbindin mRNA levels were found. CONCLUSIONS A reduction in the plasticity of synaptic terminals supports the hypothesis that their reduced modifiability may contribute to neuropathology and working memory deficits in schizophrenia.
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Affiliation(s)
- Samantha J. Fung
- Schizophrenia Research Institute, Sydney, Australia,Neuroscience Research Australia, Sydney, Australia,School of Medical Sciences, University of New South Wales, Sydney, Australia
| | | | - Cynthia Shannon Weickert
- Schizophrenia Research Institute, Sydney, Australia,Neuroscience Research Australia, Sydney, Australia,School of Psychiatry, University of New South Wales, Australia
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22
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The neuropeptide VGF is reduced in human bipolar postmortem brain and contributes to some of the behavioral and molecular effects of lithium. J Neurosci 2010; 30:9368-80. [PMID: 20631166 DOI: 10.1523/jneurosci.5987-09.2010] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Recent studies demonstrate that the neuropeptide VGF (nonacronymic) is regulated in the hippocampus by antidepressant therapies and animal models of depression and that acute VGF treatment has antidepressant-like activity in animal paradigms. However, the role of VGF in human psychiatric disorders is unknown. We now demonstrate using in situ hybridization that VGF is downregulated in bipolar disorder in the CA region of the hippocampus and Brodmann's area 9 of the prefrontal cortex. The mechanism of VGF in relation to LiCl was explored. Both LiCl intraperitoneally and VGF intracerebroventricularly reduced latency to drink in novelty-induced hypophagia, and LiCl was not effective in VGF(+/-) mice, suggesting that VGF may contribute to the effects of LiCl in this behavioral procedure that responds to chronic antidepressant treatment. VGF by intrahippocampal injection also had novel activity in an amphetamine-induced hyperlocomotion assay, thus mimicking the actions of LiCl injected intraperitoneally in a system that phenocopies manic-like behavior. Moreover, VGF(+/-) mice exhibited increased locomotion after amphetamine treatment and did not respond to LiCl, suggesting that VGF is required for the effects of LiCl in curbing the response to amphetamine. Finally, VGF delivered intracerebroventricularly in vivo activated the same signaling pathways as LiCl and is necessary for the induction of mitogen-activated protein kinase and Akt by LiCl, thus lending insight into the molecular mechanisms underlying the actions of VGF. The dysregulation of VGF in bipolar disorder as well as the behavioral effects of the neuropeptide similar to LiCl suggests that VGF may underlie the pathophysiology of bipolar disorder.
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Wong BKY, Hossain SM, Trinh E, Ottmann GA, Budaghzadeh S, Zheng QY, Simpson EM. Hyperactivity, startle reactivity and cell-proliferation deficits are resistant to chronic lithium treatment in adult Nr2e1(frc/frc) mice. GENES BRAIN AND BEHAVIOR 2010; 9:681-94. [PMID: 20497236 DOI: 10.1111/j.1601-183x.2010.00602.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The NR2E1 region on Chromosome 6q21-22 has been repeatedly linked to bipolar disorder (BP) and NR2E1 has been associated with BP, and more specifically bipolar I disorder (BPI). In addition, patient sequencing has shown an enrichment of rare candidate-regulatory variants. Interestingly, mice carrying either spontaneous (Nr2e1(frc) ) or targeted (Tlx(-) ) deletions of Nr2e1 (here collectively known as Nr2e1-null) show similar neurological and behavioral anomalies, including hypoplasia of the cerebrum, reduced neural stem cell proliferation, extreme aggression and deficits in fear conditioning; these are the traits that have been observed in some patients with BP. Thus, NR2E1 is a positional and functional candidate for a role in BP. However, no Nr2e1-null mice have been fully evaluated for behaviors used to model BP in rodents or pharmacological responses to drugs effective in treating BP symptoms. In this study we examine Nr2e1(frc/frc) mice, homozygous for the spontaneous deletion, for abnormalities in activity, learning and information processing, and cell proliferation; these are the phenotypes that are either affected in patients with BP or commonly assessed in rodent models of BP. The effect of lithium, a drug used to treat BP, was also evaluated for its ability to attenuate Nr2e1(frc/frc) behavioral and neural stem cell-proliferation phenotypes. We show for the first time that Nr2e1-null mice exhibit extreme hyperactivity in the open field as early as postnatal day 18 and in the home cage, deficits in open-field habituation and passive avoidance, and surprisingly, an absence of acoustic startle. We observed a reduction in neural stem/progenitor cell proliferation in Nr2e1(frc/frc) mice, similar to that seen in other Nr2e1-null strains. These behavioral and cell-proliferation phenotypes were resistant to chronic-adult-lithium treatment. Thus, Nr2e1(frc/frc) mice exhibit behavioral traits used to model BP in rodents, but our results do not support Nr2e1(frc/frc) mice as pharmacological models for BP.
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Affiliation(s)
- B K Y Wong
- Centre for Molecular Medicine and Therapeutics at the Child & Family Research Institute, and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
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Early parental deprivation in the marmoset monkey produces long-term changes in hippocampal expression of genes involved in synaptic plasticity and implicated in mood disorder. Neuropsychopharmacology 2009; 34:1381-94. [PMID: 18615010 PMCID: PMC2669475 DOI: 10.1038/npp.2008.106] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
In mood disorder, early stressors including parental separation are vulnerability factors, and hippocampal involvement is prominent. In common marmoset monkeys, daily parental deprivation during infancy produces a prodepressive state of increased basal activity and reactivity in stress systems and mild anhedonia that persists at least to adolescence. Here we examined the expression of eight genes, each implicated in neural plasticity and in the pathophysiology of mood disorder, in the hippocampus of these same adolescent marmosets, relative to their normally reared sibling controls. We also measured hippocampal volume. Early deprivation led to decreases in hippocampal growth-associated protein-43 (GAP-43) mRNA, serotonin 1A receptor (5-HT(1A)R) mRNA and binding ([3H]WAY100635), and to increased vesicular GABA transporter mRNA. Brain-derived neurotrophic factor (BDNF), synaptophysin, vesicular glutamate transporter 1 (VGluT1), microtubule-associated protein-2, and spinophilin transcripts were unchanged. There were some correlations with in vivo biochemical and behavioral indices, including VGluT1 mRNA with reward-seeking behavior, and serotonin 1A receptor mRNA with CSF cortisol. Early deprivation did not affect hippocampal volume. We conclude that early deprivation in a nonhuman primate, in the absence of subsequent stressors, has a long-term effect on the hippocampal expression of genes implicated in synaptic function and plasticity. The reductions in GAP-43 and serotonin 1A receptor expressions are comparable with findings in mood disorder, supporting the possibility that the latter reflect an early developmental contribution to disease vulnerability. Equally, the negative results suggest that other features of mood disorder, such as decreased hippocampal volume and BDNF expression, are related to different aspects of the pathophysiological process.
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Martinowich K, Schloesser RJ, Manji HK. Bipolar disorder: from genes to behavior pathways. J Clin Invest 2009; 119:726-36. [PMID: 19339764 DOI: 10.1172/jci37703] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Bipolar disorder (BPD) is a devastating illness that is characterized by recurrent episodes of mania and depression. In addition to these cyclic episodes, individuals with BPD exhibit changes in psychovegetative function, cognitive performance, and general health and well being. In this article we draw from neuroimaging findings in humans, postmortem data, and human genetic and pharmacological studies as well as data from animal models of behavior to discuss the neurobiology of BPD. We conclude with a synthesis of where the field stands and with suggestions and strategies for future areas of study to further increase our conceptual understanding of this complex illness.
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Affiliation(s)
- Keri Martinowich
- Johnson & Johnson Pharmaceutical Research and Development, 1125 Trenton-Harbourton Road, E32000, Titusville, New Jersey 08560, USA.
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Martinowich K, Schloesser RJ, Manji HK. Bipolar disorder: from genes to behavior pathways. J Clin Invest 2009. [PMID: 19339764 DOI: 10.1172/jci37703.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Bipolar disorder (BPD) is a devastating illness that is characterized by recurrent episodes of mania and depression. In addition to these cyclic episodes, individuals with BPD exhibit changes in psychovegetative function, cognitive performance, and general health and well being. In this article we draw from neuroimaging findings in humans, postmortem data, and human genetic and pharmacological studies as well as data from animal models of behavior to discuss the neurobiology of BPD. We conclude with a synthesis of where the field stands and with suggestions and strategies for future areas of study to further increase our conceptual understanding of this complex illness.
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Affiliation(s)
- Keri Martinowich
- Johnson & Johnson Pharmaceutical Research and Development, 1125 Trenton-Harbourton Road, E32000, Titusville, New Jersey 08560, USA.
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Targeting the hippocampal mossy fiber synapse for the treatment of psychiatric disorders. Mol Neurobiol 2009; 39:24-36. [PMID: 19130314 DOI: 10.1007/s12035-008-8049-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2008] [Accepted: 12/12/2008] [Indexed: 01/09/2023]
Abstract
It is widely known that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain. This neurogenesis has been implicated in depression and antidepressant treatments. Recent evidence also suggests that the dentate gyrus is involved in the neuropathology and pathophysiology of schizophrenia and other related psychiatric disorders. Especially, abnormal neuronal development in the dentate gyrus may be a plausible risk factor for the diseases. The synapse made by the mossy fiber, the output fiber of the dentate gyrus, plays a critical role in regulating neuronal activity in its target CA3 area. The mossy fiber synapse is characterized by remarkable activity-dependent short-term synaptic plasticity that is established during the postnatal development and is supposed to be central to the functional role of the mossy fiber. Any defects, including developmental abnormalities, in the dentate gyrus and drugs acting on the dentate gyrus can modulate the mossy fiber-CA3 synaptic transmission, which may eventually affect hippocampal functions. In this paper, I review recent evidence for involvement of the dentate gyrus and mossy fiber synapse in psychiatric disorders and discuss potential importance of drugs targeting the mossy fiber synapse either directly or indirectly in the therapeutic treatments of psychiatric disorders.
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Abstract
The hippocampus and amygdala are key limbic regions for memory formation and emotion modulation that are potentially involved in the cognitive and affective symptoms of bipolar disorder. Here we discuss the most consistent MRI literature in bipolar disorder, focusing on the role of the hippocampus and amygdala. In child and adolescent patients, a unique pattern of abnormalities has begun to emerge, with volume deficits in the hippocampus and amygdala already detectable early in the illness course. In adults, it is unclear whether hippocampal volumes are abnormal, whereas the amygdala is reported to be larger and hyperactive to external emotional stimuli. However, available findings are often conflicting, and most studies suffer from limitations. Future longitudinal magnetic resonance studies should focus on juvenile patients; first-episode, drug-free patients; and unaffected family members. Jointly with genetic, postmortem, and neuropsychological studies, these studies will be extremely valuable in separating state from trait brain abnormalities and further characterizing the pathophysiology of bipolar disorder.
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Perinatal Oxygen Restriction Does Not Result in Reduced Rat Frontal Cortex Synaptophysin Protein Levels at Adulthood as Opposed to Postmortem Findings in Schizophrenia. J Mol Neurosci 2008; 37:60-6. [DOI: 10.1007/s12031-008-9120-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2008] [Accepted: 06/04/2008] [Indexed: 11/25/2022]
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Schloesser RJ, Huang J, Klein PS, Manji HK. Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 2008; 33:110-33. [PMID: 17912251 DOI: 10.1038/sj.npp.1301575] [Citation(s) in RCA: 162] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Bipolar disorder (BPD) is characterized by recurrent episodes of disturbed affect including mania and depression as well as changes in psychovegetative function, cognitive performance, and general health. A growing body of data suggests that BPD arises from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits. Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In addition, commonly used mood-stabilizing drugs that are effective in treating BPD have been shown to target intracellular signaling pathways that control synaptic plasticity and cellular resilience. In this article we draw on clinical, preclinical, neuroimaging, and post-mortem data to discuss the neurobiology of BPD within a conceptual framework while highlighting the role of neuroplasticity in the pathophysiology and treatment of this disorder.
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Affiliation(s)
- Robert J Schloesser
- Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA
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Frey BN, Andreazza AC, Nery FG, Martins MR, Quevedo J, Soares JC, Kapczinski F. The role of hippocampus in the pathophysiology of bipolar disorder. Behav Pharmacol 2007; 18:419-30. [PMID: 17762510 DOI: 10.1097/fbp.0b013e3282df3cde] [Citation(s) in RCA: 122] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Bipolar disorder (BD) is thought to be associated with abnormalities within discrete brain regions associated with emotional regulation, particularly in fronto-limbic-subcortical circuits. Several reviews have addressed the involvement of the prefrontal cortex in the pathophysiology of BD, whereas little attention has been given to the role of the hippocampus. This study critically reviews data from brain imaging, postmortem, neuropsychological, and preclinical studies, which suggested hippocampal abnormalities in BD. Most of the structural brain imaging studies did not find changes in hippocampal volume in BD, although a few studies suggested that anatomical changes might be restricted to the psychotic, pediatric, or unmedicated BD subgroups. Functional imaging studies showed abnormal brain activation in the hippocampus and its closely related regions during emotional, attentional, and memory tasks. This is consistent with neuropsychological findings that revealed a wide range of cognitive disturbances during acute mood episodes and a significant impairment in declarative memory during remission. Postmortem studies indicate abnormal glutamate and GABA transmission in the hippocampus of BD patients, whereas data from preclinical studies suggest that the regulation of hippocampal plasticity and survival might be associated with the therapeutic effects of mood stabilizers. In conclusion, the available evidence suggests that the hippocampus plays an important role in the pathophysiology of BD.
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Affiliation(s)
- Benicio N Frey
- Bipolar Disorders Program and Laboratory of Molecular Psychiatry, Hospital de Clinicas de Porto Alegre, Rio Grande do Sul, Brazil.
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Hammonds MD, Shim SS, Feng P, Calabrese JR. Effects of subchronic lithium treatment on levels of BDNF, Bcl-2 and phospho-CREB in the rat hippocampus. Basic Clin Pharmacol Toxicol 2007; 100:356-9. [PMID: 17448124 DOI: 10.1111/j.1742-7843.2007.00058.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Although it has been proposed that exposure to lithium up-regulates brain-derived neurotrophic factor (BDNF), B-cell leukaemia/lymphoma 2 protein (Bcl-2) and cyclic AMP-response element-binding protein (CREB), and these molecules are involved in the neuroplastic actions and clinical efficacy of the drug, the several lines of evidence suggest that the lithium-induced up-regulation of these molecules has not been consistently confirmed. Few studies have examined the effects of lithium exposure on the regulation of these molecules in the dentate gyrus (DG) and area CA1 in the hippocampus. We examined the effects of subchronic lithium treatment on the levels of BDNF, Bcl-2 and phosphorylated CREB in the DG and area CA1. We administered LiCl intraperitoneally (1 mEq/kg per day) to adult rats for 14 days, killed animals in 24 hr after the last administration of the drug, and determined the tissue levels of BDNF, Bcl-2 and pCREB in the DG and area CA1. Subchronic lithium treatment for 14 days did not significantly alter the levels of BDNF, Bcl-2 or phosphorylated CREB in the DG and area CA1 in the hippocampus. This study indicates that the lithium-induced up-regulation of these molecules may be various depending on the duration of lithium exposure and particular brain regions exposed to the drug.
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Affiliation(s)
- Michael D Hammonds
- Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH 44106, USA
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