{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:52:09Z","timestamp":1768510329206,"version":"3.49.0"},"posted":{"date-parts":[[2024,1,28]]},"group-title":"Neuroscience","reference-count":165,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,12]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity, and their dysfunction is consistently observed in myriad brain diseases. To understand how immune complement dysregulation \u2013 a prevalent locus of brain disease etiology \u2013 in PV cells may drive disease pathogenesis, we have developed a transgenic mouse line that permits cell-type specific overexpression of the schizophrenia-associated complement component 4 (\n                  <jats:italic>C4<\/jats:italic>\n                  ) gene. We found that overexpression of mouse\n                  <jats:italic>C4<\/jats:italic>\n                  (\n                  <jats:italic>mC4<\/jats:italic>\n                  ) in PV cells causes sex-specific behavioral alterations and concomitant deficits in synaptic connectivity and excitability of PV cells of the prefrontal cortex. Using a computational network, we demonstrated that these microcircuit deficits led to hyperactivity and disrupted neural communication. Finally, pan-neuronal overexpression of\n                  <jats:italic>mC4<\/jats:italic>\n                  failed to evoke the same deficits in behavior as PV-specific\n                  <jats:italic>mC4<\/jats:italic>\n                  overexpression, suggesting that\n                  <jats:italic>C4<\/jats:italic>\n                  perturbations in fast-spiking neurons are more harmful to brain function than pan-neuronal alterations. Together, these results provide a causative link between\n                  <jats:italic>C4<\/jats:italic>\n                  and the vulnerability of PV cells in brain disease.\n                <\/jats:p>","DOI":"10.1101\/2024.01.27.575409","type":"posted-content","created":{"date-parts":[[2024,1,28]],"date-time":"2024-01-28T22:10:19Z","timestamp":1706479819000},"source":"Crossref","is-referenced-by-count":0,"title":["Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9352-8225","authenticated-orcid":false,"given":"Luke A.","family":"Fournier","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7097-7593","authenticated-orcid":false,"given":"Rhushikesh A.","family":"Phadke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Salgado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4401-6501","authenticated-orcid":false,"given":"Alison","family":"Brack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9879-1549","authenticated-orcid":false,"given":"Jian Carlo","family":"Nocon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Bolshakova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaylyn R.","family":"Grant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole M. 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