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bioRxiv · 10.1101/2024.01.27.575409

Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction.

Fournier, L. A.·Phadke, R. A.·Salgado, M.·Brack, A.·Bolshakova, S.·Grant, J. R.·Padro Luna, N. M.·Cruz Martin, A.
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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 dysregulation - a prevalent locus of brain disease etiology - 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 (C4) gene. We found that overexpression of mouse C4 (mC4) 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 mC4 failed to evoke the same deficits in behavior as PV-specific mC4 overexpression, suggesting that C4 perturbations in fast-spiking neurons are more harmful to brain function than pan-neuronal alterations. Together, these results provide a causative link between C4 and the vulnerability of PV cells in brain disease.

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Fournier, L. A., Phadke, R. A., Salgado, M., Brack, A., Bolshakova, S., Grant, J. R., Padro Luna, N. M., Cruz Martin, A.. 2024-01-28. Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction.. https://doi.org/10.1101/2024.01.27.575409

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