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A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function
Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset sch...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612534/ https://www.ncbi.nlm.nih.gov/pubmed/34818031 http://dx.doi.org/10.1126/sciadv.abf6935 |
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author | Xiao, Mei-Fang Roh, Seung-Eon Zhou, Jiechao Chien, Chun-Che Lucey, Brendan P. Craig, Michael T. Hayes, Lindsay N. Coughlin, Jennifer M. Leweke, F. Markus Jia, Min Xu, Desheng Zhou, Weiqiang Conover Talbot, C. Arnold, Don B. Staley, Melissa Jiang, Cindy Reti, Irving M. Sawa, Akira Pelkey, Kenneth A. McBain, Chris J. Savonenko, Alena Worley, Paul F. |
author_facet | Xiao, Mei-Fang Roh, Seung-Eon Zhou, Jiechao Chien, Chun-Che Lucey, Brendan P. Craig, Michael T. Hayes, Lindsay N. Coughlin, Jennifer M. Leweke, F. Markus Jia, Min Xu, Desheng Zhou, Weiqiang Conover Talbot, C. Arnold, Don B. Staley, Melissa Jiang, Cindy Reti, Irving M. Sawa, Akira Pelkey, Kenneth A. McBain, Chris J. Savonenko, Alena Worley, Paul F. |
author_sort | Xiao, Mei-Fang |
collection | PubMed |
description | Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress. |
format | Online Article Text |
id | pubmed-8612534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-86125342021-12-06 A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function Xiao, Mei-Fang Roh, Seung-Eon Zhou, Jiechao Chien, Chun-Che Lucey, Brendan P. Craig, Michael T. Hayes, Lindsay N. Coughlin, Jennifer M. Leweke, F. Markus Jia, Min Xu, Desheng Zhou, Weiqiang Conover Talbot, C. Arnold, Don B. Staley, Melissa Jiang, Cindy Reti, Irving M. Sawa, Akira Pelkey, Kenneth A. McBain, Chris J. Savonenko, Alena Worley, Paul F. Sci Adv Neuroscience Schizophrenia is a polygenetic disorder whose clinical onset is often associated with behavioral stress. Here, we present a model of disease pathogenesis that builds on our observation that the synaptic immediate early gene NPTX2 is reduced in cerebrospinal fluid of individuals with recent onset schizophrenia. NPTX2 plays an essential role in maintaining excitatory homeostasis by adaptively enhancing circuit inhibition. NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses and is coupled to circadian behavior. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. Modeling NPTX2 loss of function results in failure of parvalbumin interneurons in their adaptive contribution to behavioral stress, and animals exhibit multiple neuropsychiatric domains. Because the genetics of schizophrenia encompasses diverse proteins that contribute to excitatory synapse plasticity, the identified vulnerability of NPTX2 function can provide a framework for assessing the impact of genetics and the intersection with stress. American Association for the Advancement of Science 2021-11-24 /pmc/articles/PMC8612534/ /pubmed/34818031 http://dx.doi.org/10.1126/sciadv.abf6935 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Neuroscience Xiao, Mei-Fang Roh, Seung-Eon Zhou, Jiechao Chien, Chun-Che Lucey, Brendan P. Craig, Michael T. Hayes, Lindsay N. Coughlin, Jennifer M. Leweke, F. Markus Jia, Min Xu, Desheng Zhou, Weiqiang Conover Talbot, C. Arnold, Don B. Staley, Melissa Jiang, Cindy Reti, Irving M. Sawa, Akira Pelkey, Kenneth A. McBain, Chris J. Savonenko, Alena Worley, Paul F. A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function |
title | A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function |
title_full | A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function |
title_fullStr | A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function |
title_full_unstemmed | A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function |
title_short | A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function |
title_sort | biomarker-authenticated model of schizophrenia implicating nptx2 loss of function |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612534/ https://www.ncbi.nlm.nih.gov/pubmed/34818031 http://dx.doi.org/10.1126/sciadv.abf6935 |
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