Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction
| Autor: | Frances S. Hausmann, Kevin Liu Kot, Lisa N. Kretsge, SaraAnn Rosenthal, Rhushikesh A. Phadke, Yenyu Liu, Balaji Sriram, Alberto Cruz-Martín, Tushare Jinadasa, Giovanna Antognetti, Borislav Dejanovic, Elena R. Newmark, James Gilbert, Jungjoon Lee, Ashley L. Comer, William W. Yen, Thanh P. H. Nguyen |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Aging Dendritic spine Cell Communication Biochemistry Pathogenesis Mice 0302 clinical medicine Animal Cells Neural Pathways Medicine and Health Sciences Biology (General) Prefrontal cortex Cells Cultured Mice Knockout Neurons Mammals General Neuroscience Eukaryota Brain Complement C4 Transfection Pathophysiology Up-Regulation Schizophrenia Vertebrates Hyperexpression Techniques Female Cellular Types Cellular Structures and Organelles Anatomy General Agricultural and Biological Sciences Research Article QH301-705.5 Prefrontal Cortex Glial Cells Biology Research and Analysis Methods Rodents Green Fluorescent Protein General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Gene Expression and Vector Techniques medicine Animals Social Behavior Molecular Biology Techniques Microglial Cells Molecular Biology Gene Molecular Biology Assays and Analysis Techniques General Immunology and Microbiology Organisms Biology and Life Sciences Proteins Cell Biology Neuronal Dendrites medicine.disease Mice Inbred C57BL Luminescent Proteins Electrophysiology 030104 developmental biology Animals Newborn Cellular Neuroscience Amniotes Lysosomes Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | PLoS Biology, Vol 18, Iss 1, p e3000604 (2020) PLoS Biology |
| ISSN: | 1545-7885 |
| DOI: | 10.1371/journal.pbio.3000604 |
| Popis: | 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. Elevated expression of the gene encoding complement C4 is associated with an enhanced risk of schizophrenia, but the mechanism underlying this link is unclear. This study shows that overexpression of the C4 gene in mice leads to mis-wiring of the prefrontal cortex and deficits in social interactions. |
| Databáze: | OpenAIRE |
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