Reduced gene dosage of the psychiatric risk geneCacna1cis associated with impairments in hypothalamic-pituitary-adrenal axis activity in rats

Abstract

AbstractCommon and rare variation inCACNA1Cgene expression has been consistently associated with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression, however the underlying biological pathways that cause this association have yet to be fully determined. In this study, we present evidence that rats with a reduced gene dosage ofCacna1chave increased basal corticosterone levels in the periphery and reducedNr3c1gene expression in the hippocampus and hypothalamus. These results are consistent with an effect ofCacna1cdosage on hypothalamus-pituitary-adrenal (HPA) axis function. We also show that the reduction ofNr3c1in the hippocampus may be caused by epigenetic modification of exon 17ofNr3c1, including the reduced interaction with the histone modifying markers H3K4me3 and H3K27ac. HeterozygousCacna1crats additionally show increased anxiety behaviours. These results support an association ofCacna1cheterozygosity with the altered activity of the HPA axis and function in the resting state and this may be a predisposing mechanism that contributes to the increased risk of psychiatric disorders with stress.