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

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

Abstract

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
Full text:(VoR) Version of Record
First Live Deposit - 05 November 2018
Available under License - Creative Commons Attribution.
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Full text:(VoR) Version of Record
Available under License - Creative Commons Attribution.
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1093/schbul/sby146
Publisher statement:© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Record Created:05 Nov 2018 09:28
Last Modified:12 Sep 2019 09:44

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