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For: Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci 2005;30:325-33. [PMID: 15950877 DOI: 10.1016/j.tibs.2005.04.004] [Citation(s) in RCA: 249] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2005] [Revised: 03/18/2005] [Accepted: 04/13/2005] [Indexed: 01/22/2023]

For:	Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci 2005;30:325-33. [PMID: 15950877 DOI: 10.1016/j.tibs.2005.04.004] [Citation(s) in RCA: 249] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2005] [Revised: 03/18/2005] [Accepted: 04/13/2005] [Indexed: 01/22/2023]

Number

Cited by Other Article(s)

Schukarucha Gomes A, Ellis CE, Spigelman AF, Dos Santos T, Maghera J, Suzuki K, MacDonald PE. Molecular correlates of glycine receptor activity in human β cells. Mol Metab 2025;96:102156. [PMID: 40258441 PMCID: PMC12059332 DOI: 10.1016/j.molmet.2025.102156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 04/07/2025] [Accepted: 04/16/2025] [Indexed: 04/23/2025] Open

Abstract

OBJECTIVES

Glycine acts in an autocrine positive feedback loop in human β cells through its ionotropic receptors (GlyRs). In type 2 diabetes (T2D), islet GlyR activity is impaired by unknown mechanisms. We sought to investigate if the GlyR dysfunction in T2D is replicated by hyperglycemia per se, and to further characterize its action in β cells and islets.

METHODS

GlyR-mediated currents were measured using whole-cell patch-clamp in human β cells from donors with or without T2D, or after high glucose (15 mM) culture. We also correlated glycine-induced current amplitude with transcript expression levels through patch-seq. The expression of the GlyR α1, α3, and β subunit mRNA splice variants was compared between islets from donors with and without T2D, and after high glucose culture. Insulin secretion from human islets was measured in the presence or absence of the GlyR antagonist strychnine.

RESULTS

Although gene expression of GlyRs was decreased in T2D islets, and β cell GlyR-mediated currents were smaller, we found no evidence for a shift in GlyR subunit splicing. Glycine-induced currents are also reduced after 48 h culture of islets from donors without diabetes in high glucose, where we also find the reduction of the α1 subunit expression, but an increase in the α3 subunit. We discovered that glycine-evoked currents are highly heterogeneous amongst β cells, inversely correlate with donor HbA1c, and are significantly correlated to the expression of 92 different transcripts and gene regulatory networks (GRNs) that include CREB3(+), RREB1(+) and ZNF697(+). Finally, glucose-stimulated insulin secretion is decreased in the presence of the GlyR antagonist strychnine.

CONCLUSIONS

We demonstrate that glucose can modulate GlyR expression, and that the current decrease in T2D is likely due to the receptor gene expression downregulation, and not a change in transcript splicing. Moreover, we define a previously unknown set of genes and regulons that are correlated to GlyR-mediated currents and could be involved in GlyR downregulation in T2D. Among those we validate the negative impact of EIF4EBP1 expression on GlyR activity.

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Perrotta C, Carnovale C, Pozzi M, De Palma C, Cervia D, Nobile M, Clementi E. Antipsychotics and dietary interventions: Pharmacodynamics, pharmacokinetics, and synergisms in therapy. Pharmacol Rev 2025;77:100061. [PMID: 40412008 DOI: 10.1016/j.pharmr.2025.100061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 04/18/2025] [Accepted: 04/19/2025] [Indexed: 05/27/2025] Open

Abstract

Antipsychotic (AP) medications are the primary treatment for severe mental illnesses, including schizophrenia and severe mood disorders. APs are currently categorized into typical or first-generation APs and atypical or second-generation APs. Although both first-generation and second-generation APs are considered effective in treating psychotic symptoms in severe mental disorders, they differ in their mechanisms, treatment strategies, and side effect profiles. Because of their potential motor and metabolic side effects, which often compromise patient adherence and clinical outcomes, whether and how to use APs remains controversial. The use of dietary interventions in combination with APs is emerging as a viable strategy to reduce AP adverse effects while maintaining their efficacy and enhance patient adherence to treatment. In contrast to drugs that possess a well defined molecular mechanism of action, dietary interventions act in pleiotropic ways by nature. While providing a holistic approach to patient care this pleiotropy needs to be analyzed and systematized to enhance the efficacy and safety of the combination of them with APs. Guidelines for this type of treatment are still needed. In this review, we explore the pharmacological properties, therapeutic applications, and limitations of APs, and discuss the potential benefits and limitations of those dietary interventions that are employed to improve the efficacy and counteract side effects of APs discussing also their mechanisms of action. Finally, we critically discuss the main results of clinical studies combining APs and dietary interventions and provide a view on future directions in terms of research and clinical use of these combinations. SIGNIFICANCE STATEMENT: Antipsychotic drugs are useful in a variety of psychiatric conditions, yet their use is hampered by issues of efficacy and safety. An important step toward therapy optimization is their use in combination with dietary interventions (ie, dietary supplements and nutraceuticals) that have shown promising results in clinical trials.

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Origüela V, Gázquez A, López-Andreo MJ, Bueno-Vargas P, Vurma M, López-Pedrosa JM, Leyshon BJ, Kuchan M, Chan JP, Larqué E. Effects of new lipid ingredients during pregnancy and lactation on rat offspring brain gene expression. Food Funct 2025;16:1720-1730. [PMID: 39660590 DOI: 10.1039/d4fo04425h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2024]

Cooley Coleman JA, Moffitt BA, Bridges WC, Jones K, May M, Skinner C, Friez MJ, Skinner SA, Schwartz CE, Boccuto L. A novel approach to metabolic profiling in case models of MECP2-related disorders. Metab Brain Dis 2025;40:124. [PMID: 39945871 PMCID: PMC11825590 DOI: 10.1007/s11011-025-01546-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/26/2025] [Indexed: 02/16/2025]

Choi H, An YK, Lee CJ, Song CU, Kim EJ, Lee CE, Cho SJ, Eyun SI. Genome assembly, gene content, and plastic gene expression responses to salinity changes in the Brackishwater Clam (Corbicula japonica) from a dynamic estuarine environment. JOURNAL OF HAZARDOUS MATERIALS 2025;483:136627. [PMID: 39616841 DOI: 10.1016/j.jhazmat.2024.136627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 11/01/2024] [Accepted: 11/21/2024] [Indexed: 01/28/2025]

Galambos AR, Essmat N, Lakatos PP, Szücs E, Boldizsár I, Abbood SK, Karádi DÁ, Kirchlechner-Farkas JM, Király K, Benyhe S, Riba P, Tábi T, Harsing LG, Zádor F, Al-Khrasani M. Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine. Int J Mol Sci 2024;25:11136. [PMID: 39456918 PMCID: PMC11508341 DOI: 10.3390/ijms252011136] [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] [Revised: 10/11/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open

Affiliation(s)

Anna Rita Galambos Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Nariman Essmat Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Péter P. Lakatos Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.) Department of Pharmacodynamics, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
Edina Szücs Institute of Genetics, HUN-REN Biological Research Centre, Temesvári krt. 62, H-6726 Szeged, Hungary;
Imre Boldizsár Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Sarah Kadhim Abbood Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Dávid Á. Karádi Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Judit Mária Kirchlechner-Farkas Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Kornél Király Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Sándor Benyhe HUN-REN Biological Research Centre, Institute of Biochemistry, Temesvári krt. 62, H-6726 Szeged, Hungary;
Pál Riba Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Tamás Tábi Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.) Department of Pharmacodynamics, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary
Laszlo G. Harsing Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)
Ferenc Zádor Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.)
Mahmoud Al-Khrasani Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1085 Budapest, Hungary; (A.R.G.); (N.E.); (I.B.J.); (S.K.A.); (D.Á.K.); (J.M.K.-F.); (K.K.); (P.R.); (L.G.H.J.) Center for Pharmacology and Drug Research & Development, Semmelweis University, Üllői út 26., H-1085 Budapest, Hungary; (P.P.L.); (T.T.)

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Guo X, Zhang X, Li M, Peng Y, Wang Z, Liu J. Preliminary screening of biomarkers and drug candidates in a mouse model of β-thalassemia based on quasi-targeted metabolomics. Front Physiol 2024;15:1452558. [PMID: 39247159 PMCID: PMC11377281 DOI: 10.3389/fphys.2024.1452558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 08/06/2024] [Indexed: 09/10/2024] Open

Parmeggiani B, Signori MF, Cecatto C, Frusciante MR, Marcuzzo MB, Souza DG, Ribeiro RT, Seminotti B, Gomes de Souza DO, Ribeiro CAJ, Wajner M, Leipnitz G. Glycine disrupts myelin, glutamatergic neurotransmission, and redox homeostasis in a neonatal model for non ketotic hyperglycinemia. Biochimie 2024;219:21-32. [PMID: 37541567 DOI: 10.1016/j.biochi.2023.07.022] [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: 04/10/2023] [Revised: 06/26/2023] [Accepted: 07/30/2023] [Indexed: 08/06/2023]

Affiliation(s)

Belisa Parmeggiani Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Marian Flores Signori Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Cristiane Cecatto Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Marina Rocha Frusciante Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Manuela Bianchin Marcuzzo Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Débora Guerini Souza Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil
Rafael Teixeira Ribeiro Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Bianca Seminotti Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
Diogo Onofre Gomes de Souza Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
César Augusto João Ribeiro Natural and Humanities Sciences Center, Universidade Federal do ABC, São Bernardo do Campo, SP, 09606-070, Brazil
Moacir Wajner Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
Guilhian Leipnitz Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

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Izidoro Ribeiro R, Almeida Carvalho G, Almeida Chiareli R, Vieira de Assis Lima I, Quaglio Bellozi PM, Oliveira-Lima OC, Oliveira Giacomelli Á, Birbrair A, Santiago Gomez R, Pinheiro de Oliveira AC, Ulrich H, Cunha Xavier Pinto M. Glycine transporter-1 inhibition by NFPS promotes neuroprotection against striatal damage models. Neurosci Lett 2024;826:137715. [PMID: 38460902 DOI: 10.1016/j.neulet.2024.137715] [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: 12/24/2023] [Revised: 03/04/2024] [Accepted: 03/06/2024] [Indexed: 03/11/2024]

Stanca S, Rossetti M, Bokulic Panichi L, Bongioanni P. The Cellular Dysfunction of the Brain-Blood Barrier from Endothelial Cells to Astrocytes: The Pathway towards Neurotransmitter Impairment in Schizophrenia. Int J Mol Sci 2024;25:1250. [PMID: 38279249 PMCID: PMC10816922 DOI: 10.3390/ijms25021250] [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: 12/30/2023] [Revised: 01/17/2024] [Accepted: 01/18/2024] [Indexed: 01/28/2024] Open

Wang X, Yue M, Cheung JPY, Cheung PWH, Fan Y, Wu M, Wang X, Zhao S, Khanshour AM, Rios JJ, Chen Z, Wang X, Tu W, Chan D, Yuan Q, Qin D, Qiu G, Wu Z, Zhang TJ, Ikegawa S, Wu N, Wise CA, Hu Y, Luk KDK, Song YQ, Gao B. Impaired glycine neurotransmission causes adolescent idiopathic scoliosis. J Clin Invest 2024;134:e168783. [PMID: 37962965 PMCID: PMC10786698 DOI: 10.1172/jci168783] [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: 01/12/2023] [Accepted: 11/08/2023] [Indexed: 11/16/2023] Open

Affiliation(s)

Xiaolu Wang Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, China School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Ming Yue School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Jason Pui Yin Cheung Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China Department of Orthopaedics and Traumatology, University of Hong Kong–Shenzhen Hospital, Shenzhen, China
Prudence Wing Hang Cheung Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Yanhui Fan School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Meicheng Wu School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Xiaojun Wang Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Sen Zhao Department of Orthopaedic Surgery, Department of Medical Research Center, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital (PUMCH) and Chinese Academy of Medical Sciences, Beijing, China
Anas M. Khanshour Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children (SRC), Dallas, Texas, USA
Jonathan J. Rios Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children (SRC), Dallas, Texas, USA Eugene McDermott Center for Human Growth and Development, Departments of Orthopaedic Surgery and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Zheyi Chen School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Xiwei Wang Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Wenwei Tu Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Danny Chan School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
Qiuju Yuan Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Tai Po, Hong Kong, China
Dajiang Qin Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Tai Po, Hong Kong, China
Guixing Qiu Department of Orthopaedic Surgery, Department of Medical Research Center, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital (PUMCH) and Chinese Academy of Medical Sciences, Beijing, China
Zhihong Wu Department of Orthopaedic Surgery, Department of Medical Research Center, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital (PUMCH) and Chinese Academy of Medical Sciences, Beijing, China
Terry Jianguo Zhang Department of Orthopaedic Surgery, Department of Medical Research Center, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital (PUMCH) and Chinese Academy of Medical Sciences, Beijing, China
Shiro Ikegawa Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
Nan Wu Department of Orthopaedic Surgery, Department of Medical Research Center, Key Laboratory of Big Data for Spinal Deformities, State Key Laboratory of Complex Severe and Rare Diseases, Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital (PUMCH) and Chinese Academy of Medical Sciences, Beijing, China
Carol A. Wise Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children (SRC), Dallas, Texas, USA Eugene McDermott Center for Human Growth and Development, Departments of Orthopaedic Surgery and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA
Yong Hu Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China Department of Orthopaedics and Traumatology, University of Hong Kong–Shenzhen Hospital, Shenzhen, China
Keith Dip Kei Luk Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China
You-Qiang Song School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China Department of Medicine, University of Hong Kong–Shenzhen Hospital, Shenzhen, China State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
Bo Gao School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, China School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China Department of Orthopaedics and Traumatology, University of Hong Kong–Shenzhen Hospital, Shenzhen, China Centre for Translational Stem Cell Biology, Tai Po, Hong Kong, China Key Laboratory of Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong, China

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Rose CR, Verkhratsky A. Sodium homeostasis and signalling: The core and the hub of astrocyte function. Cell Calcium 2024;117:102817. [PMID: 37979342 DOI: 10.1016/j.ceca.2023.102817] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 10/20/2023] [Indexed: 11/20/2023]

Cortese K, Gagliani MC, Raiteri L. Interactions between Glycine and Glutamate through Activation of Their Transporters in Hippocampal Nerve Terminals. Biomedicines 2023;11:3152. [PMID: 38137373 PMCID: PMC10740625 DOI: 10.3390/biomedicines11123152] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/14/2023] [Accepted: 11/17/2023] [Indexed: 12/24/2023] Open

Abstract

Evidence supports the pathophysiological relevance of crosstalk between the neurotransmitters Glycine and Glutamate and their close interactions; some reports even support the possibility of Glycine-Glutamate cotransmission in central nervous system (CNS) areas, including the hippocampus. Functional studies with isolated nerve terminals (synaptosomes) permit us to study transporter-mediated interactions between neurotransmitters that lead to the regulation of transmitter release. Our main aims here were: (i) to investigate release-regulating, transporter-mediated interactions between Glycine and Glutamate in hippocampal nerve terminals and (ii) to determine the coexistence of transporters for Glycine and Glutamate in these terminals. Purified synaptosomes, analyzed at the ultrastructural level via electron microscopy, were used as the experimental model. Mouse hippocampal synaptosomes were prelabeled with [3H]D-Aspartate or [3H]Glycine; the release of radiolabeled tracers was monitored with the superfusion technique. The main findings were that (i) exogenous Glycine stimulated [3H]D-Aspartate release, partly by activation of GlyT1 and in part, unusually, through GlyT2 transporters and that (ii) D-Aspartate stimulated [3H]glycine release by a process that was sensitive to Glutamate transporter blockers. Based on the features of the experimental model used, it is suggested that functional transporters for Glutamate and Glycine coexist in a small subset of hippocampal nerve terminals, a condition that may also be compatible with cotransmission; glycinergic and glutamatergic transporters exhibit different functions and mediate interactions between the neurotransmitters. It is hoped that increased information on Glutamate-Glycine interactions in different areas, including the hippocampus, will contribute to a better knowledge of drugs acting at "glycinergic" targets, currently under study in relation with different CNS pathologies.

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Aguayo-Cerón KA, Sánchez-Muñoz F, Gutierrez-Rojas RA, Acevedo-Villavicencio LN, Flores-Zarate AV, Huang F, Giacoman-Martinez A, Villafaña S, Romero-Nava R. Glycine: The Smallest Anti-Inflammatory Micronutrient. Int J Mol Sci 2023;24:11236. [PMID: 37510995 PMCID: PMC10379184 DOI: 10.3390/ijms241411236] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 06/30/2023] [Indexed: 07/30/2023] Open

El fadili M, Er-rajy M, Imtara H, Noman OM, Mothana RA, Abdullah S, Zerougui S, Elhallaoui M. QSAR, ADME-Tox, molecular docking and molecular dynamics simulations of novel selective glycine transporter type 1 inhibitors with memory enhancing properties. Heliyon 2023;9:e13706. [PMID: 36865465 PMCID: PMC9971180 DOI: 10.1016/j.heliyon.2023.e13706] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 02/02/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023] Open

Pharmacokinetic profile of bitopertin, a selective GlyT₁ inhibitor, in the rat. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023;396:1053-1060. [PMID: 36633618 DOI: 10.1007/s00210-022-02378-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 12/29/2022] [Indexed: 01/13/2023]

Cross-Linking and Functional Analyses for Dimerization of a Cysteine Mutant of Glycine Transporter 1. Int J Mol Sci 2022;23:ijms232416157. [PMID: 36555800 PMCID: PMC9781295 DOI: 10.3390/ijms232416157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/10/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open

A comprehensive review on bioavailability, safety and antidepressant potential of natural bioactive components from tea. Food Res Int 2022;158:111540. [DOI: 10.1016/j.foodres.2022.111540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/12/2022] [Accepted: 06/18/2022] [Indexed: 11/22/2022]

Intestinal microbiome and metabolome changes induced by sevoflurane, propofol, and sevoflurane-propofol anaesthesia in patients undergoing nephrectomy. Br J Anaesth 2022;129:e38-e40. [PMID: 35725658 DOI: 10.1016/j.bja.2022.04.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 04/15/2022] [Accepted: 04/27/2022] [Indexed: 11/22/2022] Open

Bi T, Zhang L, Zhan L, Feng R, Zhao T, Ren W, Hang T, Zhou W, Lu X. Integrated Analyses of Microbiomics and Metabolomics Explore the Effect of Gut Microbiota Transplantation on Diabetes-Associated Cognitive Decline in Zucker Diabetic Fatty Rats. Front Aging Neurosci 2022;14:913002. [PMID: 35721013 PMCID: PMC9204715 DOI: 10.3389/fnagi.2022.913002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/18/2022] [Indexed: 11/13/2022] Open

Zhao S, Chi A, Wan B, Liang J. Differential Metabolites and Metabolic Pathways Involved in Aerobic Exercise Improvement of Chronic Fatigue Symptoms in Adolescents Based on Gas Chromatography-Mass Spectrometry. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022;19:ijerph19042377. [PMID: 35206569 PMCID: PMC8872503 DOI: 10.3390/ijerph19042377] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 02/12/2022] [Accepted: 02/16/2022] [Indexed: 12/03/2022]

Abstract

Studies have found that the prevalence of chronic fatigue syndrome (CFS) in adolescents has continued to increase over the years, affecting learning and physical health. High school is a critical stage for adolescents to grow and mature. There are inadequate detection and rehabilitation methods for CFS due to an insufficient understanding of the physiological mechanisms of CFS. The purpose of this study was to evaluate the effect and metabolic mechanisms of an aerobic running intervention program for high school students with CFS. Forty-six male high school students with CFS were randomly assigned to the exercise intervention group (EI) and control group (CFS). Twenty-four age- and sex-matched healthy male students were recruited as healthy controls (HCs). The EI group received the aerobic intervention for 12 weeks, three times a week, in 45-min sessions; the CFS group maintained their daily routines as normal. The outcome measures included fatigue symptoms and oxidation levels. Keratin was extracted from the nails of all participants, and the oxidation level was assessed by measuring the content of 3-Nitrotyrosine (3-NT) in the keratin by ultraviolet spectrophotometry. All participants’ morning urine was collected to analyze urinary differential metabolites by the GC-MS technique before and after the intervention, and MetaboAnalyst 5.0 was used for pathway analysis. Compared with before the intervention, the fatigue score and 3-NT level in the EI group were significantly decreased after the intervention. The CFS group was screened for 20 differential metabolites involving the disruption of six metabolic pathways, including arginine biosynthesis, glycerolipid metabolism, pentose phosphate pathway, purine metabolism, β-alanine metabolism, and arginine and proline metabolism. After the intervention, 21 differential metabolites were screened, involved in alterations in three metabolic pathways: beta-alanine metabolism, pentose phosphate metabolism, and arginine and proline metabolism. Aerobic exercise was found to lessen fatigue symptoms and oxidative levels in students with CFS, which may be related to the regulation of putrescine (arginine and proline metabolism), 6-Phospho-D-Gluconate (starch and sucrose metabolism pathway), and Pentose (phosphate metabolism pathway).

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Shimizu-Okabe C, Kobayashi S, Kim J, Kosaka Y, Sunagawa M, Okabe A, Takayama C. Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord. Int J Mol Sci 2022;23:ijms23020834. [PMID: 35055019 PMCID: PMC8776010 DOI: 10.3390/ijms23020834] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 12/15/2022] Open

Bozzo M, Costa S, Obino V, Bachetti T, Marcenaro E, Pestarino M, Schubert M, Candiani S. Functional Conservation and Genetic Divergence of Chordate Glycinergic Neurotransmission: Insights from Amphioxus Glycine Transporters. Cells 2021;10:cells10123392. [PMID: 34943900 PMCID: PMC8699752 DOI: 10.3390/cells10123392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/22/2021] [Accepted: 11/25/2021] [Indexed: 11/24/2022] Open

Ji P, Li CC, Wei YM, Hua YL, Yao WL, Wu FL, Zhang XS, Yuan ZW, Zhao NS, Zhang YH, Wen YQ. A new method providing complementary explanation of the blood-enriching function and mechanism of unprocessed Angelica sinensis and its four kinds of processed products based on tissue-integrated metabolomics and confirmatory analysis. Biomed Chromatogr 2021;36:e5252. [PMID: 34591996 DOI: 10.1002/bmc.5252] [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: 05/20/2021] [Revised: 09/15/2021] [Accepted: 09/20/2021] [Indexed: 11/05/2022]

Hoffmann C, Evcüman S, Neumaier F, Zlatopolskiy BD, Humpert S, Bier D, Holschbach M, Schulze A, Endepols H, Neumaier B. [¹⁸F]ALX5406: A Brain-Penetrating Prodrug for GlyT1-Specific PET Imaging. ACS Chem Neurosci 2021;12:3335-3346. [PMID: 34449193 DOI: 10.1021/acschemneuro.1c00284] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open

Affiliation(s)

Chris Hoffmann Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany Institute of Radiochemistry and Experimental Molecular Imaging, University of Cologne, Faculty of Medicine, and University Hospital Cologne, 50937 Cologne, Germany
Sibel Evcüman Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Felix Neumaier Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany Institute of Radiochemistry and Experimental Molecular Imaging, University of Cologne, Faculty of Medicine, and University Hospital Cologne, 50937 Cologne, Germany
Boris D. Zlatopolskiy Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany Institute of Radiochemistry and Experimental Molecular Imaging, University of Cologne, Faculty of Medicine, and University Hospital Cologne, 50937 Cologne, Germany
Swen Humpert Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Dirk Bier Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Marcus Holschbach Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Annette Schulze Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany
Heike Endepols Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany Institute of Radiochemistry and Experimental Molecular Imaging, University of Cologne, Faculty of Medicine, and University Hospital Cologne, 50937 Cologne, Germany Nuclear Medicine Department, University of Cologne, Faculty of Medicine, and University Hospital Cologne, 50937 Cologne, Germany
Bernd Neumaier Nuclear Chemistry (INM-5), Institute of Neuroscience and Medicine, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany Institute of Radiochemistry and Experimental Molecular Imaging, University of Cologne, Faculty of Medicine, and University Hospital Cologne, 50937 Cologne, Germany Max Planck Institute of Metabolism Research, 50931 Cologne, Germany

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Sherwood MW, Oliet SHR, Panatier A. NMDARs, Coincidence Detectors of Astrocytic and Neuronal Activities. Int J Mol Sci 2021;22:7258. [PMID: 34298875 PMCID: PMC8307462 DOI: 10.3390/ijms22147258] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 12/18/2022] Open

Ayala-Lopez N, Watts SW. Physiology and Pharmacology of Neurotransmitter Transporters. Compr Physiol 2021;11:2279-2295. [PMID: 34190339 DOI: 10.1002/cphy.c200035] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]

Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling. Biomolecules 2021;11:biom11060864. [PMID: 34200954 PMCID: PMC8230656 DOI: 10.3390/biom11060864] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/23/2022] Open

Abstract

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na⁺/Cl⁻-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain.

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Cutruzzolà F, Bouzidi A, Liberati FR, Spizzichino S, Boumis G, Macone A, Rinaldo S, Giardina G, Paone A. The Emerging Role of Amino Acids of the Brain Microenvironment in the Process of Metastasis Formation. Cancers (Basel) 2021;13:2891. [PMID: 34207731 PMCID: PMC8227515 DOI: 10.3390/cancers13122891] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/03/2021] [Accepted: 06/07/2021] [Indexed: 12/25/2022] Open

Kelly L, Seifi M, Ma R, Mitchell SJ, Rudolph U, Viola KL, Klein WL, Lambert JJ, Swinny JD. Identification of intraneuronal amyloid beta oligomers in locus coeruleus neurons of Alzheimer's patients and their potential impact on inhibitory neurotransmitter receptors and neuronal excitability. Neuropathol Appl Neurobiol 2021;47:488-505. [PMID: 33119191 DOI: 10.1111/nan.12674] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/14/2020] [Accepted: 10/16/2020] [Indexed: 12/22/2022]

Chang CY, Luo DZ, Pei JC, Kuo MC, Hsieh YC, Lai WS. Not Just a Bystander: The Emerging Role of Astrocytes and Research Tools in Studying Cognitive Dysfunctions in Schizophrenia. Int J Mol Sci 2021;22:ijms22105343. [PMID: 34069523 PMCID: PMC8160762 DOI: 10.3390/ijms22105343] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/14/2021] [Accepted: 05/14/2021] [Indexed: 12/16/2022] Open

Ethanol inhibition of lateral orbitofrontal cortex neuron excitability is mediated via dopamine D1/D5 receptor-induced release of astrocytic glycine. Neuropharmacology 2021;192:108600. [PMID: 33965399 DOI: 10.1016/j.neuropharm.2021.108600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/16/2021] [Accepted: 04/30/2021] [Indexed: 01/25/2023]

Abstract

Recent findings from this laboratory demonstrate that ethanol reduces the intrinsic excitability of orbitofrontal cortex (OFC) neurons via activation of strychnine-sensitive glycine receptors. Although the mechanism linking ethanol to the release of glycine is currently unknown, astrocytes are a source of neurotransmitters including glycine and activation of dopamine D1-like receptors has been reported to enhance extracellular levels of glycine via a functional reversal of the astrocytic glycine transporter GlyT1. We recently reported that like ethanol, dopamine or a D1/D5 receptor agonist increases a tonic current in lateral OFC (lOFC) neurons. Therefore, in this study, we used whole-cell patch-clamp electrophysiology to examine whether ethanol inhibition of OFC spiking involves the release of glycine from astrocytes and whether this release is dopamine receptor dependent. Ethanol, applied acutely, decreased spiking of lOFC neurons and this effect was blocked by antagonists of GlyT1, the norepinephrine transporter or D1-like but not D2-like receptors. Ethanol enhanced the tonic current of OFC neurons and occluded the effect of dopamine suggesting that ethanol and dopamine may share a common pathway. Altering astrocyte function by suppressing intracellular astrocytic calcium signaling or blocking the astrocyte-specific Kir4.1 potassium channels reduced but did not completely abolish ethanol inhibition of OFC neuron firing. However, when both astrocytic calcium signaling and Kir4.1 channels were inhibited, ethanol had no effect on firing. Ethanol inhibition was also prevented by inhibitors of phospholipase C and conventional isoforms of protein kinase C (cPKC) previously shown to block D1R-induced GlyT1 reversal and PKC inhibition of Kir4.1 channels. Finally, the membrane potential of OFC astrocytes was depolarized by bath application of a Kir4.1 blocker, a D1 agonist or ethanol and ethanol effect was blocked by a D1 antagonist. Together, these findings suggest that acute ethanol inhibits OFC neuron excitability via a D1 receptor-mediated dysregulation of astrocytic glycine transport.

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Barsch L, Werdehausen R, Leffler A, Eulenburg V. Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol. Biomolecules 2021;11:biom11040493. [PMID: 33805979 PMCID: PMC8064320 DOI: 10.3390/biom11040493] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/20/2021] [Accepted: 03/22/2021] [Indexed: 11/25/2022] Open

A Discrete Glycinergic Neuronal Population in the Ventromedial Medulla That Induces Muscle Atonia during REM Sleep and Cataplexy in Mice. J Neurosci 2021;41:1582-1596. [PMID: 33372061 DOI: 10.1523/jneurosci.0688-20.2020] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 12/13/2020] [Accepted: 12/15/2020] [Indexed: 12/20/2022] Open

Abstract

During rapid eye movement (REM) sleep, anti-gravity muscle tone and bodily movements are mostly absent, because somatic motoneurons are inhibited by descending inhibitory pathways. Recent studies showed that glycine/GABA neurons in the ventromedial medulla (VMM; Gly^VMM neurons) play an important role in generating muscle atonia during REM sleep (REM-atonia). However, how these REM-atonia-inducing neurons interconnect with other neuronal populations has been unknown. In the present study, we first identified a specific subpopulation of Gly^VMM neurons that play an important role in induction of REM-atonia by virus vector-mediated tracing in male mice in which glycinergic neurons expressed Cre recombinase. We found these neurons receive direct synaptic input from neurons in several brain stem regions, including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD; Glu^SLD neurons). Silencing this circuit by specifically expressing tetanus toxin light chain (TeTNLC) resulted in REM sleep without atonia. This manipulation also caused a marked decrease in time spent in cataplexy-like episodes (CLEs) when applied to narcoleptic orexin-ataxin-3 mice. We also showed that Gly^VMM neurons play an important role in maintenance of sleep. This present study identified a population of glycinergic neurons in the VMM that are commonly involved in REM-atonia and cataplexy.SIGNIFICANCE STATEMENT We identified a population of glycinergic neurons in the ventral medulla that plays an important role in inducing muscle atonia during rapid eye movement (REM) sleep. It sends axonal projections almost exclusively to motoneurons in the spinal cord and brain stem except to those that innervate extraocular muscles, while other glycinergic neurons in the same region also send projections to other regions including monoaminergic nuclei. Furthermore, these neurons receive direct inputs from several brainstem regions including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD). Genetic silencing of this pathway resulted in REM sleep without atonia and a decrease of cataplexy when applied to narcoleptic mice. This work identified a neural population involved in generating muscle atonia during REM sleep and cataplexy.

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Wilson KA, Mostyn SN, Frangos ZJ, Shimmon S, Rawling T, Vandenberg RJ, O'Mara ML. The allosteric inhibition of glycine transporter 2 by bioactive lipid analgesics is controlled by penetration into a deep lipid cavity. J Biol Chem 2021;296:100282. [PMID: 33450225 PMCID: PMC7949037 DOI: 10.1016/j.jbc.2021.100282] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 01/06/2021] [Accepted: 01/08/2021] [Indexed: 01/07/2023] Open

Doucette KA, Chaiyasit P, Calkins DL, Martinez KN, Van Cleave C, Knebel CA, Tongraar A, Crans DC. The Interfacial Interactions of Glycine and Short Glycine Peptides in Model Membrane Systems. Int J Mol Sci 2020;22:ijms22010162. [PMID: 33375246 PMCID: PMC7795424 DOI: 10.3390/ijms22010162] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/20/2022] Open

Xu P, Ning J, Jiang Q, Li C, Yan J, Zhao L, Gao H, Zheng H. Region-specific metabolic characterization of the type 1 diabetic brain in mice with and without cognitive impairment. Neurochem Int 2020;143:104941. [PMID: 33333211 DOI: 10.1016/j.neuint.2020.104941] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 12/08/2020] [Accepted: 12/12/2020] [Indexed: 11/28/2022]

Mademont-Soler I, Casellas-Vidal D, Trujillo A, Espuña-Capote N, Maroto A, García-González MDM, Ruiz MD, Diego-Álvarez D, Queralt X, Perapoch J, Obón M. GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms. Am J Med Genet A 2020;185:476-485. [PMID: 33269555 DOI: 10.1002/ajmg.a.61996] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/05/2020] [Accepted: 11/07/2020] [Indexed: 01/13/2023]

Guillén M, Mora AJ, Belandria LM, Seijas LE, Ramírez JW, Burgos JL, Rincón L, Delgado GE. Two conformational polymorphs of 4-methylhippuric acid. ACTA CRYSTALLOGRAPHICA SECTION B, STRUCTURAL SCIENCE, CRYSTAL ENGINEERING AND MATERIALS 2020;76:1077-1091. [PMID: 33289719 DOI: 10.1107/s2052520620013773] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 10/14/2020] [Indexed: 06/12/2023]

Abstract

4-Methylhippuric acid {systematic name: 2-[(4-methylbenzoyl)amino]ethanoic acid}, a p-xylene excreted metabolite with a backbone containing three rotatable bonds (R-bonds), is likely to produce more than one stable molecular structure in the solid state. In this work, we prepared polymorph I by slow solvent evaporation (plates with Z' = 1) and polymorph II by mechanical grinding (plates with Z' = 2). Potential energy surface (PES) analysis, rotating the molecule about the C-C-N-C torsion angle, shows four conformational energy basins. The second basin, with torsion angles near -73°, agree with the conformations adopted by polymorph I and molecules A of polymorph II, and the third basin at 57° matched molecules B of polymorph II. The energy barrier between these basins is 27.5 kJ mol^-1. Superposition of the molecules of polymorphs I and II rendered a maximum r.m.s. deviation of 0.398 Å. Polymorphs I and II are therefore true conformational polymorphs. The crystal packing of polymorph I consists of C(5) chains linked by N-H...O interactions along the a axis and C(7) chains linked by O-H...O interactions along the b axis. In polymorph II, two molecules (A with A or B with B) are connected by two acid-amide O-H...O interactions rendering R₂²(14) centrosymmetric dimers. These dimers alternate to pile up along the b axis linked by N-H...O interactions. A Hirshfeld surface analysis localized weaker noncovalent interactions, C-H...O and C-H...π, with contact distances close to the sum of the van der Waals radii. Electron density at a local level using the Quantum Theory of Atoms in Molecules (QTAIM) and the Electron Localization Function (ELF), or a semi-local level using noncovalent interactions, was used to rank interactions. Strong closed shell interactions in classical O-H...O and N-H...O hydrogen bonds have electron density highly localized on bond critical points. Weaker delocalized electron density is seen around the p-methylphenyl rings associated with dispersive C-H...π and H...H interactions.

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Hudson AR, Santora VJ, Petroski RE, Almos TA, Anderson G, Barido R, Basinger J, Bellows CL, Bookser BC, Broadbent NJ, Cabebe C, Chai CK, Chen M, Chow S, Chung DM, Heger L, Danks AM, Freestone GC, Gitnick D, Gupta V, Hoffmaster C, Kaplan AP, Kennedy MR, Lee D, Limberis J, Ly K, Mak CC, Masatsugu B, Morse AC, Na J, Neul D, Nikpur J, Renick J, Sebring K, Sevidal S, Tabatabaei A, Wen J, Xia S, Yan Y, Yoder ZW, Zook D, Peters M, Breitenbucher JG. Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties. Bioorg Med Chem Lett 2020;30:127214. [PMID: 32527538 DOI: 10.1016/j.bmcl.2020.127214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/22/2020] [Accepted: 04/23/2020] [Indexed: 11/24/2022]

Affiliation(s)

Andrew R Hudson Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States.
Vincent J Santora Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Robert E Petroski Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Theresa A Almos Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Gary Anderson Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Richard Barido Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Jillian Basinger Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Chris L Bellows Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Brett C Bookser Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Nicola J Broadbent Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Clifford Cabebe Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Chih-Kun Chai Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Mi Chen Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Stephine Chow Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
De Michael Chung Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Lindsay Heger Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Anne M Danks Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Graeme C Freestone Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Dany Gitnick Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Varsha Gupta Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Christine Hoffmaster Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Alan P Kaplan Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Michael R Kennedy Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Dong Lee Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
James Limberis Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Kiev Ly Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Chi Ching Mak Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Brittany Masatsugu Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Andrew C Morse Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Jim Na Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
David Neul Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
John Nikpur Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Joel Renick Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Kristen Sebring Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Samantha Sevidal Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Ali Tabatabaei Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Jenny Wen Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Shouzhen Xia Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Yingzhuo Yan Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Zachary W Yoder Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Douglas Zook Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
Marco Peters Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States
J Guy Breitenbucher Dart Neuroscience, 12278 Scripps Summit Dr, San Diego, CA 92131, United States

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Mostyn SN, Sarker S, Muthuraman P, Raja A, Shimmon S, Rawling T, Cioffi CL, Vandenberg RJ. Photoswitchable ORG25543 Congener Enables Optical Control of Glycine Transporter 2. ACS Chem Neurosci 2020;11:1250-1258. [PMID: 32191428 PMCID: PMC7206614 DOI: 10.1021/acschemneuro.9b00655] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open

Verkhratsky A, Rose CR. Na⁺-dependent transporters: The backbone of astroglial homeostatic function. Cell Calcium 2019;85:102136. [PMID: 31835178 DOI: 10.1016/j.ceca.2019.102136] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 11/30/2019] [Accepted: 11/30/2019] [Indexed: 01/30/2023]

Gao H, Jiang Q, Ji H, Ning J, Li C, Zheng H. Type 1 diabetes induces cognitive dysfunction in rats associated with alterations of the gut microbiome and metabolomes in serum and hippocampus. Biochim Biophys Acta Mol Basis Dis 2019;1865:165541. [DOI: 10.1016/j.bbadis.2019.165541] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/23/2019] [Accepted: 08/26/2019] [Indexed: 12/14/2022]

Matte A, Federti E, Winter M, Koerner A, Harmeier A, Mazer N, Tomka T, Di Paolo ML, De Falco L, Andolfo I, Beneduce E, Iolascon A, Macias-Garcia A, Chen JJ, Janin A, Lebouef C, Turrini F, Brugnara C, De Franceschi L. Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia. JCI Insight 2019;4:130111. [PMID: 31593554 DOI: 10.1172/jci.insight.130111] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 10/02/2019] [Indexed: 01/09/2023] Open

Affiliation(s)

Alessandro Matte Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Verona, Policlinico GB Rossi, Verona, Italy
Enrica Federti Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Verona, Policlinico GB Rossi, Verona, Italy
Michael Winter Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Annette Koerner Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Anja Harmeier Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Norman Mazer Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Tomas Tomka Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Maria Luisa Di Paolo Department of Molecular Medicine, University of Padova, Padova, Italy
Luigia De Falco Department of Molecular Medicine and Medical Biotechnology, University Federico II and CEINGE, Naples, Italy
Immacolata Andolfo Department of Molecular Medicine and Medical Biotechnology, University Federico II and CEINGE, Naples, Italy
Elisabetta Beneduce Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Verona, Policlinico GB Rossi, Verona, Italy
Achille Iolascon Department of Molecular Medicine and Medical Biotechnology, University Federico II and CEINGE, Naples, Italy
Alejandra Macias-Garcia Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Jane-Jane Chen Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Anne Janin INSERM, U1165, Paris, France.,Université Paris 7 - Denis Diderot, Paris, France.,AP-HP, Hôpital Saint-Louis, Paris, France
Christhophe Lebouef INSERM, U1165, Paris, France.,Université Paris 7 - Denis Diderot, Paris, France.,AP-HP, Hôpital Saint-Louis, Paris, France
Franco Turrini Department of Oncology, University of Torino, Torino, Italy
Carlo Brugnara Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Lucia De Franceschi Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Verona, Policlinico GB Rossi, Verona, Italy

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Mostyn SN, Wilson KA, Schumann-Gillett A, Frangos ZJ, Shimmon S, Rawling T, Ryan RM, O'Mara ML, Vandenberg RJ. Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics. eLife 2019;8:e47150. [PMID: 31621581 PMCID: PMC6797481 DOI: 10.7554/elife.47150] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 09/30/2019] [Indexed: 01/01/2023] Open

Kitzenmaier A, Schaefer N, Kasaragod VB, Polster T, Hantschmann R, Schindelin H, Villmann C. The P429L loss of function mutation of the human glycine transporter 2 associated with hyperekplexia. Eur J Neurosci 2019;50:3906-3920. [DOI: 10.1111/ejn.14533] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 07/23/2019] [Accepted: 07/25/2019] [Indexed: 12/20/2022]

Prisciandaro JJ, Schacht JP, Prescot AP, Brenner HM, Renshaw PF, Brown TR, Anton RF. Evidence for a unique association between fronto-cortical glycine levels and recent heavy drinking in treatment naïve individuals with alcohol use disorder. Neurosci Lett 2019;706:207-210. [PMID: 31108129 PMCID: PMC6621545 DOI: 10.1016/j.neulet.2019.05.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/06/2019] [Accepted: 05/16/2019] [Indexed: 12/26/2022]

Abstract

Although the neurotransmitters/modulators glutamate and, more recently, glycine have been implicated in the development and maintenance of Alcohol Use Disorder (AUD) in preclinical research, human proton magnetic resonance spectroscopy (1H-MRS) studies have focused solely on the measurement of glutamate. The purpose of the present analysis was to examine the relative associations of brain glutamate and glycine levels with recent heavy drinking in 41 treatment naïve individuals with AUD using 1H-MRS. The present study is the first that we are aware of to report in vivo brain glycine levels from an investigation of addiction. Dorsal Anterior Cingulate Cortex (dACC) glutamate and glycine concentration estimates were obtained using Two-Dimensional J-Resolved Point Resolved Spectroscopy at 3 Tesla, and past 2-week summary estimates of alcohol consumption were assessed via the Timeline Followback method. Glutamate (β = -0.44, t = -3.09, p = 0.004) and glycine (β = -0.68, t = -5.72, p < 0.001) were each significantly, inversely associated with number of heavy drinking days when considered alone. However, when both variables were simultaneously entered into a single regression model, the effect of glutamate was no longer significant (β = -0.11, t = -0.81, p = 0.42) whereas the effect of glycine remained significant (β = -0.62, t = -4.38, p < 0.001). The present study extends the literature by demonstrating a unique, inverse association of brain glycine levels with recent heavy drinking in treatment naïve individuals with AUD. If replicated and extended, these data could lead to enhanced knowledge of how glycinergic systems change with alcohol consumption and AUD progression leading to pharmacological interventional/preventative strategies that modulate brain glycine levels.

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Rothenberg DO, Zhang L. Mechanisms Underlying the Anti-Depressive Effects of Regular Tea Consumption. Nutrients 2019;11:E1361. [PMID: 31212946 PMCID: PMC6627400 DOI: 10.3390/nu11061361] [Citation(s) in RCA: 97] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/03/2019] [Accepted: 06/11/2019] [Indexed: 12/19/2022] Open

Abstract

This article is a comprehensive review of the literature pertaining to the antidepressant effects and mechanisms of regular tea consumption. Meta-data supplemented with recent observational studies were first analyzed to assess the association between tea consumption and depression risk. The literature reported risk ratios (RR) were 0.69 with 95% confidence intervals of 0.62-0.77. Next, we thoroughly reviewed human trials, mouse models, and in vitro experiments to determine the predominant mechanisms underlying the observed linear relationship between tea consumption and reduced risk of depression. Current theories on the neurobiology of depression were utilized to map tea-mediated mechanisms of antidepressant activity onto an integrated framework of depression pathology. The major nodes within the network framework of depression included hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, inflammation, weakened monoaminergic systems, reduced neurogenesis/neuroplasticity, and poor microbiome diversity affecting the gut-brain axis. We detailed how each node has subsystems within them, including signaling pathways, specific target proteins, or transporters that interface with compounds in tea, mediating their antidepressant effects. A major pathway was found to be the ERK/CREB/BDNF signaling pathway, up-regulated by a number of compounds in tea including teasaponin, L-theanine, EGCG and combinations of tea catechins and their metabolites. Black tea theaflavins and EGCG are potent anti-inflammatory agents via down-regulation of NF-κB signaling. Multiple compounds in tea are effective modulators of dopaminergic activity and the gut-brain axis. Taken together, our findings show that constituents found in all major tea types, predominantly L-theanine, polyphenols and polyphenol metabolites, are capable of functioning through multiple pathways simultaneously to collectively reduce the risk of depression.

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The glycine site of NMDA receptors: A target for cognitive enhancement in psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2019;92:387-404. [PMID: 30738126 DOI: 10.1016/j.pnpbp.2019.02.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 01/29/2019] [Accepted: 02/01/2019] [Indexed: 01/05/2023]

Abstract

Cognitive dysfunction is a principal determinant of functional impairment in major depressive disorder (MDD) and often persists during periods of euthymia. Abnormalities in the glutamate system, particularly in N-methyl-d-aspartate receptors (NMDARs) activity, have been shown to contribute to both mood and cognitive symptoms in MDD. The current narrative review aims to evaluate the potential pro-cognitive effects of targeting the glycine site of NMDARs in the treatment of psychiatric disorders, with a special focus on how these results may apply to MDD. Literature databases were searched from inception to May 2018 for relevant pre-clinical and clinical studies evaluating antidepressant and pro-cognitive effects of NMDAR glycine site modulators in both MDD and non-MDD samples. Six glycine site modulators with pro-cognitive and antidepressant properties were identified: d-serine (co-agonist), d-cycloserine (partial agonist), d-alanine (co-agonist), glycine (agonist), sarcosine (co-agonist) and rapastinel (partial agonist). Preclinical animal studies demonstrated improved neuroplasticity and pro-cognitive effects with these agents. Numerous proof-of-concept clinical trials demonstrated pro-cognitive and antidepressant effects trans-diagnostically (e.g., in healthy participants, MDD, schizophrenia, anxiety disorders, major neurocognitive disorders). The generalizability of these clinical studies was limited by the small sample sizes and the paucity of studies directly evaluating cognitive effects in MDD samples, as most clinical trials were in non-MDD samples. Taken together, preliminary results suggest that the glycine site of NMDARs is a promising target to ameliorate symptoms of depression and cognitive dysfunction. Additional rigorously designed clinical studies are required to determine the cognitive effects of these agents in MDD.

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Fischer AU, Müller NIC, Deller T, Del Turco D, Fisch JO, Griesemer D, Kattler K, Maraslioglu A, Roemer V, Xu‐Friedman MA, Walter J, Friauf E. GABA is a modulator, rather than a classical transmitter, in the medial nucleus of the trapezoid body-lateral superior olive sound localization circuit. J Physiol 2019;597:2269-2295. [PMID: 30776090 PMCID: PMC6462465 DOI: 10.1113/jp277566] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 02/18/2019] [Indexed: 12/13/2022] Open

Abstract

KEY POINTS

The lateral superior olive (LSO), a brainstem hub involved in sound localization, integrates excitatory and inhibitory inputs from the ipsilateral and the contralateral ear, respectively. In gerbils and rats, inhibition to the LSO reportedly shifts from GABAergic to glycinergic within the first three postnatal weeks. Surprisingly, we found no evidence for synaptic GABA signalling during this time window in mouse LSO principal neurons. However, we found that presynaptic GABAB Rs modulate Ca2+ influx into medial nucleus of the trapezoid body axon terminals, resulting in reduced synaptic strength. Moreover, GABA elicited strong responses in LSO neurons that were mediated by extrasynaptic GABAA Rs. RNA sequencing revealed highly abundant δ subunits, which are characteristic of extrasynaptic receptors. Whereas GABA increased the excitability of neonatal LSO neurons, it reduced the excitability around hearing onset. Collectively, GABA appears to control the excitability of mouse LSO neurons via extrasynaptic and presynaptic signalling. Thus, GABA acts as a modulator, rather than as a classical transmitter.

ABSTRACT

GABA and glycine mediate fast inhibitory neurotransmission and are coreleased at several synapse types. Here we assessed the contribution of GABA and glycine in synaptic transmission between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO), two nuclei involved in sound localization. Whole-cell patch-clamp experiments in acute mouse brainstem slices at postnatal days (P) 4 and 11 during pharmacological blockade of GABAA receptors (GABAA Rs) and/or glycine receptors demonstrated no GABAergic synaptic component on LSO principal neurons. A GABAergic component was absent in evoked inhibitory postsynaptic currents and miniature events. Coimmunofluorescence experiments revealed no codistribution of the presynaptic GABAergic marker GAD65/67 with gephyrin, a postsynaptic marker for GABAA Rs, corroborating the conclusion that GABA does not act synaptically in the mouse LSO. Imaging experiments revealed reduced Ca2+ influx into MNTB axon terminals following activation of presynaptic GABAB Rs. GABAB R activation reduced the synaptic strength at P4 and P11. GABA appears to act on extrasynaptic GABAA Rs as demonstrated by application of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, a δ-subunit-specific GABAA R agonist. RNA sequencing showed high mRNA levels for the δ-subunit in the LSO. Moreover, GABA transporters GAT-1 and GAT-3 appear to control extracellular GABA. Finally, we show an age-dependent effect of GABA on the excitability of LSO neurons. Whereas tonic GABA increased the excitability at P4, leading to spike facilitation, it decreased the excitability at P11 via shunting inhibition through extrasynaptic GABAA Rs. Taken together, we demonstrate a modulatory role of GABA in the murine LSO, rather than a function as a classical synaptic transmitter.

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