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Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction
Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cel...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959572/ https://www.ncbi.nlm.nih.gov/pubmed/31935214 http://dx.doi.org/10.1371/journal.pbio.3000604 |
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author | Comer, Ashley L. Jinadasa, Tushare Sriram, Balaji Phadke, Rhushikesh A. Kretsge, Lisa N. Nguyen, Thanh P. H. Antognetti, Giovanna Gilbert, James P. Lee, Jungjoon Newmark, Elena R. Hausmann, Frances S. Rosenthal, SaraAnn Liu Kot, Kevin Liu, Yenyu Yen, William W. Dejanovic, Borislav Cruz-Martín, Alberto |
author_facet | Comer, Ashley L. Jinadasa, Tushare Sriram, Balaji Phadke, Rhushikesh A. Kretsge, Lisa N. Nguyen, Thanh P. H. Antognetti, Giovanna Gilbert, James P. Lee, Jungjoon Newmark, Elena R. Hausmann, Frances S. Rosenthal, SaraAnn Liu Kot, Kevin Liu, Yenyu Yen, William W. Dejanovic, Borislav Cruz-Martín, Alberto |
author_sort | Comer, Ashley L. |
collection | PubMed |
description | Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia patients. We find evidence that microglia-mediated synaptic engulfment is enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile and adult mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in juvenile and adult social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis. |
format | Online Article Text |
id | pubmed-6959572 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-69595722020-01-26 Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction Comer, Ashley L. Jinadasa, Tushare Sriram, Balaji Phadke, Rhushikesh A. Kretsge, Lisa N. Nguyen, Thanh P. H. Antognetti, Giovanna Gilbert, James P. Lee, Jungjoon Newmark, Elena R. Hausmann, Frances S. Rosenthal, SaraAnn Liu Kot, Kevin Liu, Yenyu Yen, William W. Dejanovic, Borislav Cruz-Martín, Alberto PLoS Biol Research Article Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is not known whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia patients. We find evidence that microglia-mediated synaptic engulfment is enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile and adult mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in juvenile and adult social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis. Public Library of Science 2020-01-14 /pmc/articles/PMC6959572/ /pubmed/31935214 http://dx.doi.org/10.1371/journal.pbio.3000604 Text en © 2020 Comer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Comer, Ashley L. Jinadasa, Tushare Sriram, Balaji Phadke, Rhushikesh A. Kretsge, Lisa N. Nguyen, Thanh P. H. Antognetti, Giovanna Gilbert, James P. Lee, Jungjoon Newmark, Elena R. Hausmann, Frances S. Rosenthal, SaraAnn Liu Kot, Kevin Liu, Yenyu Yen, William W. Dejanovic, Borislav Cruz-Martín, Alberto Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction |
title | Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction |
title_full | Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction |
title_fullStr | Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction |
title_full_unstemmed | Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction |
title_short | Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction |
title_sort | increased expression of schizophrenia-associated gene c4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959572/ https://www.ncbi.nlm.nih.gov/pubmed/31935214 http://dx.doi.org/10.1371/journal.pbio.3000604 |
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