Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction.

Autor: Comer AL; Department of Biology, Boston University, Boston, Massachusetts, United States of America.; The Graduate Program for Neuroscience, Boston University, Boston, Massachusetts, United States of America.; Neurophotonics Center, Boston University, Boston, Massachusetts, United States of America., Jinadasa T; Department of Biology, Boston University, Boston, Massachusetts, United States of America.; Neurophotonics Center, Boston University, Boston, Massachusetts, United States of America., Sriram B; Research and Early Development, Biogen, Cambridge, Massachusetts, United States of America., Phadke RA; Molecular Biology, Cell Biology and Biochemistry Program, Boston University, Boston, Massachusetts, United States of America., Kretsge LN; Department of Biology, Boston University, Boston, Massachusetts, United States of America.; The Graduate Program for Neuroscience, Boston University, Boston, Massachusetts, United States of America.; Neurophotonics Center, Boston University, Boston, Massachusetts, United States of America., Nguyen TPH; Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America., Antognetti G; Biologics Drug Discovery, Biogen, Cambridge, Massachusetts, United States of America., Gilbert JP; External Innovations and New Indications, Biogen, Cambridge, Massachusetts, United States of America., Lee J; Department of Biology, Boston University, Boston, Massachusetts, United States of America., Newmark ER; Department of Biology, Boston University, Boston, Massachusetts, United States of America., Hausmann FS; Department of Biology, Boston University, Boston, Massachusetts, United States of America., Rosenthal S; Department of Biology, Connecticut College, New London, Connecticut, United States of America., Liu Kot K; Department of Biology, Boston University, Boston, Massachusetts, United States of America., Liu Y; Biochemistry and Molecular Biology/Biotechnology Program, Boston University, Boston, Massachusetts, United States of America., Yen WW; Department of Biology, Boston University, Boston, Massachusetts, United States of America.; Department of Biomedical Engineering, Boston University, Boston, Massachusetts, United States of America., Dejanovic B; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America., Cruz-Martín A; Department of Biology, Boston University, Boston, Massachusetts, United States of America.; The Graduate Program for Neuroscience, Boston University, Boston, Massachusetts, United States of America.; Neurophotonics Center, Boston University, Boston, Massachusetts, United States of America.; Molecular Biology, Cell Biology and Biochemistry Program, Boston University, Boston, Massachusetts, United States of America.; Department Pharmacology and Experimental Therapeutics, Boston University, Boston, Massachusetts, United States of America.; Center for Systems Neuroscience, Boston University, Boston, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2020 Jan 14; Vol. 18 (1), pp. e3000604. Date of Electronic Publication: 2020 Jan 14 (Print Publication: 2020).
DOI: 10.1371/journal.pbio.3000604
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje