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

Sykes, Lucy; Haddon, Josephine; Lancaster, Thomas M.; Sykes, Arabella; Azzouni, Karima; Ihssen, Niklas; Moon, Anna L.; Lin, Tzu-Ching E.; Linden, David E.; Owen, Michael J.; O'Donovan, Michael C.; Humby, Trevor; Wilkinson, Lawrence S.; Thomas, Kerrie L.; Hall, Jeremy

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Lucy Sykes

Josephine Haddon

Thomas M. Lancaster

Arabella Sykes

Karima Azzouni

Anna L. Moon

Tzu-Ching E. Lin

David E. Linden

Michael J. Owen

Michael C. O'Donovan

Trevor Humby

Lawrence S. Wilkinson

Kerrie L. Thomas

Jeremy Hall


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.


Sykes, L., Haddon, J., Lancaster, T. M., Sykes, A., Azzouni, K., Ihssen, N., …Hall, J. (2019). Genetic Variation in the Psychiatric Risk Gene CACNA1C Modulates Reversal Learning Across Species. Schizophrenia Bulletin: The Journal of Psychoses and Related Disorders, 45(5), 1024-1032.

Journal Article Type Article
Acceptance Date Oct 10, 2018
Online Publication Date Oct 10, 2018
Publication Date Sep 30, 2019
Deposit Date Nov 4, 2018
Publicly Available Date Nov 5, 2018
Journal Schizophrenia Bulletin
Print ISSN 0586-7614
Electronic ISSN 1745-1701
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 45
Issue 5
Pages 1024-1032


Published Journal Article (Advance online version) (346 Kb)

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Copyright Statement
Advance online version © The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.<br /> This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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