T113. ULTRA-LOW DOSE OF RISPERIDONE GIVEN IN ADOLESCENCE PREVENTS STRUCTURAL BRAIN AND BEHAVIORAL ABNORMALITIES INDUCED BY GESTATIONAL OR LACTATIONAL EXPOSURE TO MATERNAL IMMUNE ACTIVATION

Abstract

Background Prenatal exposure to the viral mimic polyinosinic-polycytidilic acid (poly-I:C) has been shown to produce a wide spectrum of brain and behavioral abnormalities phenotypic of schizophrenia. We showed that prenatal poly-I:C led to increasingly widespread volumetric abnormalities that preceded the emergence of behavioral deficits, and that an ultra-low dose of risperidone (RIS) given to male offspring prior to "symptom" emergence (on PNDs 34–47), prevented both behavioral and structural abnormalities. Recently, we established a new model in which poly-I:C is administered to the nursing dams on PND4. This manipulation leads in the offspring to sexually dimorphic behavioral phenotypes in adulthood, with male but not female offspring exhibiting SCZ-like cognitive inflexibility (manifested in persistent latent inhibition [LI] and impaired reversal), and female but not male offspring exhibiting affective/hedonic deficit (manifested in increased immobility in the forced swim test [FST] and decreased saccharine preference), recapitulating the known sex bias in these disorders. These behavioral deficits are preceded by structural brain deterioration. Here, we tested whether adolescent RIS would be effective in preventing the sex-specific behavioral deficits induced by lactational poly-I:C as it is effective in preventing behavioral deficits induced by gestational poly-I:C. Methods PolyI:C (4mg/kg) or saline, was injected to pregnant dams on GD 15 or to lactating dams on PND 4. Female offspring that underwent gestational exposure (results in males were already published) and offspring of both sexes that underwent lactational exposure, were injected daily with RIS (0.045 mg/kg) at adolescence (PNDs 34–47). At adulthood all the offspring underwent in-vivo structural imaging and behavioral testing - LI and AIA in prenatal poly-I:C females and in lactational poly-I:C males, and FST in lactational polyI:C females. Results Adult females prenatally exposed to poly-I:C had disrupted LI and excessive AIA, as well as enlarged lateral ventricles and smaller hippocampal, striatal and prefrontocortical volumes. In the lactational model, poly-I:C exposed males exhibited persistent LI and hypo-response to amphetamine, and poly-I:C-exposed females exhibited increased immobility in the FST and hyper-response to amphetamine. In-vivo imaging revealed hippocampal and striatal volume reductions in both sexes at PND 70 and enlargement of LV at PND 200. Risperidone prevented poly-I:C-induced brain abnormalities as well as the emergence of behavioral abnormalities in both the prenatal and the lactational models. Discussion Ultra-low dose of risperidone administered in adolescence is effective in preventing both structural and behavioral consequences in the gestational immune activation model, and in both sexes in the lactational immune activation model. These findings provide the first evidence showing the efficacy of the same early intervention in preventing the emergence of distinct behavioral phenotypes caused by different early insults in the two sexes. Notably, the behavioral phenotypes are considered to model positive symptoms (disrupted LI and hyper-response to amphetamine, in females prenatally exposed to poly-I:C), negative/cognitive symptoms (persistent LI and hypo-response to amphetamine, in males lactationally exposed to poly-I:C), and depressive symptoms (increased immobility in FST in females lactationally exposed to poly-I:C). We conclude that the neurodevelopmentally compromised brain is remarkably plastic until "symptom" emergence, and that intervention during this pre-symptomatic vulnerability window is trans-risk factors and trans-diagnostic.