# Reduced Gene Dosage of the Psychiatric Risk Gene Cacna1c Is Associated with Impairments in Hypothalamic–Pituitary–Adrenal Axis Activity in Rats

## TL;DR

Reduced Cacna1c gene dosage in rats is linked to HPA axis dysfunction and increased anxiety, potentially explaining psychiatric disorder risk.

## Contribution

This study demonstrates a novel link between Cacna1c gene dosage and HPA axis activity in rats, providing biological insight into psychiatric risk.

## Key findings

- Rats with reduced Cacna1c gene dosage have elevated basal corticosterone levels and reduced Nr3c1 expression in the hippocampus and hypothalamus.
- Heterozygous Cacna1c rats show lower H3K4me3 and H3K27ac histone markers at Nr3c1 exon 17 without changes in exon expression.
- Cacna1c heterozygosity is associated with increased anxiety behaviors and altered HPA axis function in resting states.

## Abstract

Common and rare variation in CACNA1C gene 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 of Cacna1c have increased basal corticosterone levels in the periphery and reduced the expression of Nr3c1 encoding the glucocorticoid receptor in the hippocampus and hypothalamus. These results are consistent, with an effect of Cacna1c dosage on hypothalamus–pituitary–adrenal (HPA) axis function. Heterozygous Cacna1c rats had lower levels of the histone markers H3K4me3 and H3K27acat exon 17 of the Nr3c1 gene. These histone modifications are typically linked to increased gene expression, but here were not associated with changes in the expression of exon 17 variants under non-stress conditions. Heterozygous Cacna1c rats additionally show increased anxiety behaviours. These results support an association of Cacna1c heterozygosity 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.