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

• DOI: 10.1093/schbul/sby146
• Publication Date: 2018-09-28T20:38:06Z
• Authors: Lucy Sykes; Josephine Haddon; Thomas M Lancaster; Arabella Sykes; Karima Azzouni; Niklas Ihssen; 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
• Keywords: Adult; Male; Heterozygote; 0303 health sciences; Bipolar Disorder; Calcium Channels, L-Type; Genotype; Brain-Derived Neurotrophic Factor; Gene Expression; Genetic Variation; Prefrontal Cortex; Middle Aged; Polymerase Chain Reaction; Healthy Volunteers; Gene Knockout Techniques; 03 medical and health sciences; Gene Expression Regulation; Databases, Genetic; Animals; Humans; Female; In Situ Hybridization; Regular Articles

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 CACNA1C contributes these is however not fully known. Both disorder are associated with impairments reversal learning (RL), may contribute symptoms seen conditions. We used a translational RL paradigm investigate whether affects both humans transgenic rats. Associated changes gene expression were explored using situ hybridization quantitative PCR rats BRAINEAC online human database. Risk-associated healthy participants was RL. Consistent this finding, bearing heterozygous deletion Cacna1c impaired an analogous touchscreen task. investigated possible molecular mechanism underlying impairment found that +/- show decreased Bdnf prefrontal cortex. Examination data showed risk-associated also altered brain-derived neurotrophic factor (BDNF) cortex humans. These results indicate by impacting behavioral flexibility, potentially through regulation BDNF Tests be useful studies development therapies targeting VGCCs.