Dysregulation of parvalbumin- and calretinin-expressing neurons in the lateral septum of the Df(16)A+/- mouse model of schizophrenia

Schizophrenia is a major disabling psychiatric disease, significantly impacts patients' social functioning. The lateral septum (LS), a brain region connecting the cortex to the hypothalamus and crucial for regulating affect and social behaviors, is implicated in schizophrenia. We hypothesized that specific populations of LS neurons regulating social interactions are dysregulated during schizophrenia and leveraged the Df(16)A+/- mouse model of schizophrenia to test our hypothesis. This model contains the human 22q11 microdeletion, which in humans, confers a 30% probability to develop schizophrenia. These mice exhibit impairments in social interaction and, specifically, in social recognition reminiscent of the human patients’ symptoms.We examined LS neurons expressing calretinin (CALB2+) or parvalbumin (PV+) proteins in mutant and their wild-type (WT) littermates, observing significant gender differences in WT mice, with higher neuron densities in males. In mutant male mice, PV+ and CALB2+ neuron densities were reduced in the ventral-lateral posterior LS, a region crucial for social interaction regulation. Unlike male mice, mutant female mice showed little differences compared to WT. This strong gender bias inmice parallel human studies showing that the course of schizophrenia is more severe in male than female.We focused on CALB2+ neurons in male mice and traced the inputs-output of these neurons. Then, we used chemogenetic silencing to assess the role of CALB2+ neurons. Silencing LSCALB2 neurons impaired sociability and social recognition, similar to the social behavioral deficits exhibited by the Df(16)A+/- mutant mice. We are currently using optogenetic to excite the remaining LSCALB2 neurons and rescue these social behavioral deficits.