Gene-Environment Interaction in Transgenic Rats overexpressing human DISC1: Effects of Early Social Isolation on...

Early-life social isolation (SI) is a well-established environmental stressor associated with persistent behavioral alterations relevant to psychiatric disorders. Whether SI interacts with neurodevelopmental brain abnormalities to modify behavioral vulnerability remains unclear. We investigated the effects of post-weaning SI in transgenic rats overexpressing full-length human Disrupted-in-Schizophrenia 1 (tgDISC1), a model characterized by DISC1 protein aggregation, impaired dopamine homeostasis, and abnormal neuronal migration. Male wild-type (WT) and tgDISC1 rats were housed individually or in groups from postnatal day 21 for 28 consecutive days and evaluated using behavioral tests assessing stress-coping, self-care, locomotor activity, anxiety-like behavior, contextual fear memory, and social behavior. SI reduced grooming behavior, shortened the latency to the first immobility episode in the forced swim test, and decreased contextual freezing regardless of genotype, whereas locomotor activity and anxiety-like behavior were unaffected. Genotype-dependent differences were observed in anxiety-related measures, showing distinct performances in the Open Field and Elevated Plus Maze tests. In the social interaction test, SI selectively altered social preference, revealing a significant gene × environment interaction, indicating that neurodevelopmental brain abnormalities specifically modulated the effects of early-life SI on social behavior. Together, these findings demonstrate that early-life SI induces selective behavioral alterations, whereas DISC1-related dysfunction selectively influences the behavioral consequences of SI in the social domain rather than conferring generalized vulnerability. These results highlight the value of multidomain behavioral phenotyping in gene × environment models and identify social behavior as a sensitive marker of DISC1-related susceptibility to early-life stress, with implications for the developmental origins of psychiatric disorders.