The impact of genetic variation in Cacna1c and prepubertal stress on hippocampal function

Schizophrenia and bipolar disorder are examples of disabling psychiatric conditions caused by both genetic and environmental factors. Genome-wide association studies have consistently demonstrated that variation in the gene calcium voltage-gated channel subunit alpha1C (CACNA1C) increases risk for psychiatric disorders. Early life stress has also been reliably and convincingly associated with increased risk for schizophrenia and bipolar disorder. This thesis presents results concerning how genetic variation in Cacna1c and prepubertal stress can affect hippocampal function and structure, potentially through interacting together. PPS is shown to decrease Cacna1c in the CA1 and CA3 of the hippocampal formation, which is also seen in a small cohort of human ELS samples, suggesting a translational aspect of this work (Chapter 3). Delay, trace and unpaired auditory fear conditioning were conducted in Cacna1c+/- (Chapter 4) and PPS rats (Chapter 5) to examine how associative learning was processed within the hippocampus and amygdala in these animals. Both Cacna1c+/- rats and PPS rats demonstrate disrupted trace fear conditioning, a paradigm that explicitly requires the hippocampus. Trace conditioning has been associated with adult hippocampal neurogenesis, a process that is decreased at the cell proliferation level in Cacna1c+/- rats (Chapter 6), whereas PPS rats have increased immature neurons (Chapter 6). Environmental enrichment in Cacna1c+/- rats was not sufficient to correct these behavioural and molecular deficits (Chapter 8). Finally, Cacna1c+/- animals show PV and GAD67 expression changes in the dentate gyrus, suggesting a potential inhibitory deficit (Chapter 7). These results contribute to the literature implicating Cacna1c, stress and the hippocampus in the development of mental disorders