622. MICE CARRYING THE ARXR264Q MUTATION SHOW SEX-SPECIFIC DISRUPTIONS TO PARVALBUMIN AND SOMATOSTATIN INTERNEURON DENSITIES

Abstract Background Schizophrenia is a severely debilitating psychiatric disorder with strong genetic heritability. Our laboratory discovered a novel mutation in the aristaless-related homeobox (ARX) gene of a female with schizophrenia. The ARX gene is crucial for the migration and differentiation of GABAergic interneurons. GABAergic interneurons which express somatostatin (SST) or parvalbumin (PV) are key modulators of synchronised neural network firing critical for information processing and social recognition. Impaired cognition and disturbed neural network firing are commonly observed in schizophrenia, accompanied by reductions in PV and SST interneurons, therefore the ARX gene shows biological plausibility in terms of its relevance to schizophrenia. To further explore the causative nature of this gene mutation, we generated a mouse mutation model called ArxR264Q. This model showed sex-specific behavioural and electrophysiological phenotypes with females but not males showing social and cognitive flexibility impairments, while males but not female ArxR264Q mice show altered sensorimotor gating. Neural network activity, within the gamma frequency were disrupted specifically during social interaction tasks in the prefrontal cortex of female ArxR264Q mice. Given this electrophysiological phenotype, we hypothesised that the cells that modulate gamma oscillations, PV and SST cells, would be altered in ArxR264Q mice. Aims & Objectives This research aimed to identify whether PV and SST interneurons were altered by the ArxR264Q mutation and whether sex affected the cellular phenotype. Method Immunohistochemical procedures were performed and IMARIS software was used to evaluate PV and SST interneuron density (cells/mm2) in the prefrontal cortex (PFC), hippocampus, striatum, amygdala, subiculum, medial septum (MS) and septohippocampal pathway, areas critical to social memory and sensory processing. Results A sex-specific effect of genotype is present on SST and PV interneurons in the PFC and striatum where males demonstrate significant increases in PV (p<0.01) and somatostatin (p<0.001) densities whilst females demonstrate a significant decrease in PV cell density (p<0.001). In the amygdala, there is a sex-specific effect on PV interneurons where males display decreases in both PV and SST interneurons (p<0.05) while females show no change, and SST was reduced in ArxR264Q mice of both sexes (p<0.05). A significant effect of genotype on PV and SST interneurons in both sexes was also identified in the MS and septohippocampal pathway (p<0.05). In the subiculum, there was no effect of genotype or sex. In the hippocampus both males and females exhibit decreases in both PV (males p<0.001; females p<0.0001) and SST (males p<0.05; females p<0.0001) interneuron densities, however the decrease is more prominent in female ArxR264Q mice. Discussion & Conclusions The results suggest the mutation has disrupted PV and SST interneuron cell density in each region studied, excluding the subiculum and these cellular alterations may play a role in the behavioural phenotypes observed in the model, which are relevant to symptom domains of psychiatric disorders such as schizophrenia. In addition, we identified striking sex-specific effects on the cellular phenotypes in the PFC, striatum, amygdala, and hippocampus, highlighting the clear sexually dimorphic role of this gene.