F21. THE PHOSPHODIESTERASE-9 INHIBITOR BI 409306 ATTENUATES SOCIAL INTERACTION AND DOPAMINERGIC DEFICITS IN ADULT OFFSPRING OF POLY(I:C)-BASED MATERNAL IMMUNE ACTIVATION NEURODEVELOPMENTAL MOUSE MODEL

Abstract

Background: Maternal immune activation (MIA) is used as a neurodevelopmental model mimicking part of the behavioral and molecular deficits observed in schizophrenia. In the present study, the effects of the selective PDE9 inhibitor, BI 409306, in adult offspring from the poly(I:C)-based MIA mouse model were evaluated. Methods: Pregnant C57BL6/N mice were treated with poly(I:C) (5mg/kg, i.v.) or saline on gestation day 12. Male offspring (n=9/group) were administered orally once daily with BI 409306 (0.2, 0.5, 1mg/kg) or vehicle starting at post-natal day (PND) 70 and subjected to a battery of behavioral tests. Working memory performance, social behavior, sensorimotor processing and response to amphetamine were assessed in sequence from PND70 to PND120. Results: Maternal poly(I:C) injection induced a significant decrease in social interaction (p<0.01, one-way ANOVA followed by Fisher’s LSD) in the adult offspring. A trend was observed for potentiation of the amphetamine-induced hyperlocomotion and for decrease in pre-pulse inhibition (PPI); working memory performance was not affected. Chronic treatment with BI 409306 at the dose of 1mg/kg significantly attenuated the social interaction deficits (p<0.05) and showed a trend for a reduction of amphetamine-induced hyperlocomotion in the adult offspring. BI 409306 did not show any effects in the PPI test nor on working memory performance. Conclusions: In this study we showed that chronic treatment with the PDE9 inhibitor BI 409306 led to an attenuation of behavioral deficits induced by MIA in the mouse. The current findings support the test of BI 409306 for prevention of relapse in patients with schizophrenia (NCT03351244). Keywords: PDE9 Inhibitor, Schizophrenia, Maternal Immune Activation, Pharmacology