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Genetic variation in the psychiatric risk gene CACNA1C modulates reversal learning across species

Sykes, Lucy, Haddon, Josephine, Lancaster, Thomas M. ORCID:, Sykes, Arabella, Azzouni, Karima, Niklas, Ihssen, Moon, Anna L. ORCID:, Lin, Tzu-Ching E., Linden, David E. ORCID:, Owen, Michael J. ORCID:, O'Donovan, Michael C. ORCID:, Humby, Trevor ORCID:, Wilkinson, Lawrence S. ORCID:, Thomas, Kerrie L. ORCID: and Hall, Jeremy ORCID: 2019. Genetic variation in the psychiatric risk gene CACNA1C modulates reversal learning across species. Schizophrenia Bulletin 45 (5) , pp. 1024-1032. 10.1093/schbul/sby146

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Genetic variation in CACNA1C, 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 in CACNA1C 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 in CACNA1C 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 in CACNA1C in healthy human participants was associated with impairments in RL. Consistent with this finding, rats bearing a heterozygous deletion of Cacna1c were impaired in an analogous touchscreen RL task. We investigated the possible molecular mechanism underlying this impairment and found that Cacna1c +/- rats show decreased expression of Bdnf in prefrontal cortex. Examination of BRAINEAC data showed that human risk-associated genetic variation in CACNA1C is also associated with altered expression of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex in humans. These results indicate that genetic variation in CACNA1C may contribute to risk for schizophrenia and bipolar disorder by impacting behavioral flexibility, potentially through altered regulation of BDNF expression in the prefrontal cortex. Tests of RL may be useful for translational studies and in the development of therapies targeting VGCCs

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Publisher: Oxford University Press
ISSN: 0586-7614
Date of First Compliant Deposit: 28 September 2018
Date of Acceptance: 18 September 2018
Last Modified: 11 Oct 2023 19:38

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