Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction
Date
2024-09-20
Version
Published version
OA Version
Citation
L.A. Fournier, R.A. Phadke, M. Salgado, A. Brack, J.C. Nocon, S. Bolshakova, J.R. Grant, N.M. Padró Luna, K. Sen, A. Cruz-Martín. 2024. "Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction." iScience, Volume 27, Issue 9, pp.110800-. https://doi.org/10.1016/j.isci.2024.110800
Abstract
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 pathway dysregulation in PV cells drives disease pathogenesis, we have developed a transgenic line that permits cell-type specific overexpression of the schizophrenia-associated C4 gene. We found that overexpression of mouse C4 (mC4) in PV cells causes sex-specific alterations in anxiety-like behavior and deficits in synaptic connectivity and excitability of PFC PV cells. Using a computational model, we demonstrated that these microcircuit deficits led to hyperactivity and disrupted neural communication. Finally, pan-neuronal overexpression of mC4 failed to evoke the same deficits in behavior as PV-specific mC4 overexpression, suggesting that perturbations of this neuroimmune gene in fast-spiking neurons are especially detrimental to circuits associated with anxiety-like behavior. Together, these results provide a causative link between C4 and the vulnerability of PV cells in brain disease.
Description
License
©2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).