Influence of DISC1 genetics on brain and behavioral development of offspring exposed to Maternal immune activation

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Abstract Epidemiological data suggest that exposure to infection during pregnancy may initiate an altered trajectory of fetal brain development and increases risk of offspring neurodevelopmental disorders, including schizophrenia (SZ). Animal models of maternal immune activation (MIA) have demonstrated that experimental activation of the maternal immune system and the subsequent maternal cytokine response induces changes in offspring brain and behavioral development in domains relevant to human neurodevelopmental disorders. While many mothers have immune challenges during pregnancy, only a subset of the children born to those mothers develop neurodevelopmental disorders. This hints at the potential theory that some children may be inherently susceptible to MIA. One of the most important factors for resilience and susceptibility in MIA may be genetics, as several disorders manifest as an interaction of genetic susceptibility and environmental risk. One gene of particular interest is the DISC1 (Disrupted-in-schizophrenia-1) gene. DISC1 was discovered in large Scottish pedigree and is linked to a higher incidence of SZ and SZ spectrum disorders, bipolar disorder, and mood disorders. DISC1 has been found to be necessary for proper neurodevelopment, through associations with embryonic and adult neurogenesis, synaptic transmission, neuronal proliferation, corticogenesis, and synapse formation. Animal models of DISC1-/- have been used to characterize SZ pathophysiology and risk, as they mimic the aberrant neurodevelopment that is often seen in SZ patients. The DISC1-/- model provides an opportunity to explore gene by environment effects on MIA outcomes. Preliminary studies of DISC1-/- mice exposed to MIA have begun to uncover promising gene by environment interactions. However, relying solely on mouse models limits our ability to evaluate complex social and cognitive behaviors, two areas which are critical for understanding SZ-related phenotypes. In addition, previous MIA DISC1-/- studies have not examined the relationship of the dam’s immune response to the development of the offspring through neonatal whole brain cytokines, behavior, and adult dopamine D2 receptor levels. We propose a novel rat model to investigate the interactions between gene and environment in characterizing rats exposed to both LPS-induced MIA and the DISC1 knockout. Successful completion of the proposed aims will begin uncover how genetic susceptibility may shape MIA offspring phenotypes.