PM491. The Neurodevelopmental Profile of Group 1 Metabotropic Glutamate Receptors: Implications for Novel Therapeutics

Prenatal maternal infection represents a risk factor for schizophrenia and related disorders. In rodents, prenatal immune challenge with the viral mimetic poly(I:C) (polyriboinosinic-polyribocytidilic-acid) induces long-term behavioral deficits, highly relevant for schizophrenia and neurodevelopmental disorders. We have previously shown that the behavioral abnormalities in mice treated with poly(I:C) during late gestation are associated with significant impairments in the GABAergic transcriptome (1), one of the most robust change found in schizophrenia. Here we investigated the modulation of GABAergic markers in dorsal and ventral hippocampus of poly(I:C) treated mice, and we evaluated the effect of chronic lurasidone treatment (2) during adulthood on such parameters. Pregnant C57BL/6 mice were treated with poly(I:C) (5 mg/kg) or saline on gestation day 17. At adulthood, a cohort of mice was treated for 30 days with lurasidone at the dose of 1mg/kg/day by oral gavage. Animals were sacrificed 24h after the last drug administration and the brain regions were dissected and frozen on dry ice for the molecular analyses. We found that prenatal immune challenge was able to reduce parvalbumin protein levels in the dorsal hippocampus, an effect that was normalized by lurasidone administration. Moreover, the levels of neuroligin-2 (NLGN-2), a synaptic cell adhesion molecule involved in the stabilization and maturation of GABAergic synapses, was decreased in the dorsal hippocampus of poly(I:C) mice and that these changes were also ameliorated by lurasidone administration. Our findings demonstrate that poly(I:C)-induced immune challenge late in gestation produces enduring changes in GABAergic markers, primarily affecting the dorsal hippocampus. These changes may sustain behavioral defects produced by the prenatal infection, which are associated with an abnormal function of PV neurons. Interestingly, chronic treatment with lurasidone was able to counteract some of these changes in line with its potential to ameliorate cognitive functions that are deteriorated in psychiatric patients (2, 3).