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

Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity and thus serve an indispensable role in cognitive function and emotional regulation. Feed-forward excitatory inputs, essential for the function of PV cells, are disrupted in various neurological conditions, including schizophrenia (SCZ). However, it is not clear how disease-associated stressors such as immune dysregulation contribute to defects in particular cell types or neuronal circuits. We have developed a novel transgenic mouse line that permits conditional, cell-type specific overexpression (OE) of the immune complement component 4 ( C4 ) gene, which is highly associated with SCZ. Using this genetic approach, we demonstrate that specific global OE of mouse C4 ( mC4 ) in PV cells causes pathological anxiety-like behavior in male, but not female mice. In the male medial prefrontal cortex (mPFC), this sexually dimorphic behavioral alteration was accompanied by a reduction in excitatory inputs to fast-spiking cells and an enhancement of their inhibitory connections. Additionally, in PV cells, elevated levels of mC4 led to contrasting effects on the excitability of cortical cells. In males, PV cells and pyramidal neurons exhibited reduced excitability, whereas in females, PV cells displayed heightened excitability. Contrary to the behavioral changes seen with elevated mC4 levels in PV cells, pan-neuronal overexpression did not increase anxiety-like behaviors. This indicates that mC4 dysfunction, particularly in fast-spiking cells, has a more significant negative impact on anxiety-like behavior than widespread alterations in the neuronal complement. Consequently, by employing a novel mouse model, we have demonstrated a causal relationship between the conditional overexpression of the schizophrenia risk gene C4 in fast-spiking neurons and the susceptibility of cortical circuits in male mice, resulting in changes in behaviors associated with prefrontal cortex function.