Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species

AbstractGenetic variation inCACNA1C, which encodes the alpha-1 subunit of Cav1.2 L-type voltage-gated calcium channels (VGCCs), has been strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. How genetic variation inCACNA1C contributes to risk for these disorders is however not fully known. Both schizophrenia and bipolar disorder are associated with impairments in reversal learning (RL), which may contribute to symptoms seen in these conditions. We used a translational RL paradigm to investigate whether genetic variation inCACNA1C affects RL in both humans and transgenic rats. Associated changes in gene expression were explored using in situ hybridization and quantitative PCR in rats and the BRAINEAC online human database. Risk-associated genetic variation inCACNA1C in healthy human participants was associated with impairments in RL. Consistent with this finding, rats bearing a heterozygous deletion ofCacna1c were impaired in an analogous touchscreen RL task. We investigated the possible molecular mechanism underlying this impairment and found thatCacna1c +/ − rats show decreased expression ofBdnf in prefrontal cortex. Examination of BRAINEAC data showed that human risk-associated genetic variation inCACNA1C is also associated with altered expression of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex in humans. These results indicate that genetic variation inCACNA1C may contribute to risk for schizophrenia and bipol...
Source: Schizophrenia Bulletin - Category: Psychiatry Source Type: research