PROJECT SUMMARY/ ABSTRACT Altered GABAergic interneurons have been documented following genetic and environmental perturbations in Autism Spectrum Disorder (ASD) suggesting that GABAergic interneurons might be particularly susceptible and contribute to ASD pathophysiology. We identified Caspr2, a neuronal protein to be a target of 3 monoclonal IgG derived from mothers with anti-brain antibodies (Ab) with an ASD child, and found that ~40% of mothers with anti-brain Ab harbor anti-Caspr2 IgG. Caspr2 expression is localized during development to proliferating progenitor cells of pyramidal neurons in the ventricular zone and to the medial ganglionic eminence (MGE) where somatostatin and parvalbumin interneurons (PVI) arise. It is involved in stabilization of dendrites and synapses and is an ASD risk gene. Its brain expression is similar between females and males throughout gestation. We have demonstrated that exposure in utero to either human monoclonal anti-Caspr2 IgG or polyclonal anti-Caspr2 IgG results in male offspring with structural and behavioral alterations. Female offspring show no such alterations. Here we focus on the immunization model in which female mice are immunized with the extracellular domain of human Caspr2 and harbor endogenous polyclonal anti-Caspr2 Abs throughout gestation. Male mice exposed in utero to anti-Caspr2 IgG (“Anti-Caspr2”) exhibit a specific reduction in PVIs but not in number of other hippocampal interneurons such as somatostatin, calretinin and cholecystokinin in the CA1 region of the hippocampus compared to adjuvant immunized control mice (“Control”). The reduction in PVIs is evident at postnatal age P21 and is not accompanied by a reduction in total number of GABAergic cells. The reduction in PVIs in Anti-Caspr2 male mice is not explained by a reduction in PV progenitor cells or altered migration, as number of proliferating and apoptotic progenitor interneurons in the MGE and the number of migratory MGE interneurons is similar between Control and Anti-Caspr2 male mice. Given the contribution of PVIs to gamma oscillations, we implanted multi-electrodes in Anti-Caspr2 male mice, targeted to the striata oriens and pyramidale, and calculated relative power of the gamma band. Anti-Caspr2 male mice exhibit a significant increase in mid and high gamma oscillations. Taken together, the model permits a study of the impact of PVIs during development as they pertain to ASD. Our hypothesis is that in utero exposure to anti-Caspr2 Abs has sex specific epigenetic effects on PVI maturation, which contribute to network imbalance in male mice. We therefore propose to study: 1. Whether the reduction in PV expression in the CA1 region of the hippocampus is associated with epigenetic changes that disrupt the normal transcriptional profile of PVIs in male but not female Anti-Caspr2 mice. 2. When abnormal PVIs network patterns develop in Anti-Caspr2 mice and what are the functional consequence of disrupting PVI development using ...