Apomorphine susceptibility and prenatal infection alter neurodevelopment, synaptic density and anticipatory behavior...

Schizophrenia is a complex psychiatric disorder, driven by genetic and environmental factors. While individual risk genes have limited impact, polygenic susceptibility increases the likelihood of schizophrenia and heightens sensitivity to environmental stressors, such as prenatal immune activation. Yet, preclinical studies often focused on single-gene mutations, leaving polygenic influences largely unexplored. Using the apomorphine-susceptible (APO-SUS) rat model, which exhibits schizophrenia-like features, we investigated how polygenic susceptibility influences early neurodevelopment, synaptic density, and behavior, and how these effects are modulated by prenatal immune activation. APO-SUS rats demonstrated early neurodevelopmental abnormalities, including a reduced number and duration of separation-induced ultrasonic vocalizations (USVs), increased principal frequency of USVs, and reduced heart rate variability (HRV), indicative of heightened sympathetic dominance commonly seen in psychiatric disorders. These effects were particularly pronounced in females. Male APO-SUS rats exhibited elevated synaptophysin levels, a presynaptic marker for synaptic density, in the frontal cortex during adolescence and in the hippocampus during adulthood. Interestingly, prenatal immune activation counteracted some of these changes, preventing HRV reduction and normalizing synaptophysin levels. Male and female APO-SUS rats, as well as Wistar male rats exposed to prenatal immune activation, showed anticipatory behavior during adolescence, but not in adulthood. Our results suggest that polygenic susceptibility induces early neurodevelopmental changes and that genetic and environmental risk factors do not always act synergistically; sometimes counterbalancing each other. Future studies should explore how early neurodevelopmental changes, such as alterations in USVs and HRV, influence later behavioral outcomes in polygenic models of schizophrenia.