Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease

The Emerging Neurobiology of Bipolar Disorder

Large-scale genome-wide association studies have consistently shown that genetic variation in CACNA1C, a gene that encodes calcium voltage-gated channel subunit alpha1C, increases risk for psychiatric disorders. CACNA1C encodes the Cav1.2 subunit of voltage-gated calcium channels, which themselves have been functionally implicated in a broad spectrum of neuropsychiatric syndromes. Research has concentrated on uncovering the underlying biological mechanisms that could be responsible for this increased risk. This review presents an overview of recent findings regarding Cacna1c variation in animal models, particularly focusing on behavioral phenotypes associated with neurodevelopmental disorders such as cognition, anxiety and depressive phenotypes, and fear conditioning. The impact of reduced gene dosage of Cacna1c on adult hippocampal neurogenesis is also assessed, including new data from a novel Cacna1c+/− rat model.

/pdf/cacna1c-association-with-psychiatric-disorders-behavior-and-4zy0gc5m8g.pdf

CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis.

Robust Hi-C Maps of Enhancer-Promoter Interactions Reveal the Function of Non-coding Genome in Neural Development and Diseases.

https://link.springer.com/content/pdf/10.1007%2Fs13311-017-0532-0.pdf

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms

Calcium channel subunits, including CACNA1C, have been associated with multiple psychiatric disorders. Specifically, genome wide association studies (GWAS) have repeatedly identified the single nucleotide polymorphism (SNP) rs1006737 in intron 3 of CACNA1C to be strongly associated with schizophrenia and bipolar disorder. Here, we show that rs1006737 marks a quantitative trait locus for CACNA1C transcript levels. We test 16 SNPs in high linkage disequilibrium with rs1007637 and find one, rs4765905, consistently showing allele-dependent regulatory function in reporter assays. We find allele-specific protein binding for 13 SNPs including rs4765905. Using protein microarrays, we identify several proteins binding ≥3 SNPs, but not control sequences, suggesting possible functional interactions and combinatorial haplotype effects. Finally, using circular chromatin conformation capture, we show interaction of the disease-associated region including the 16 SNPs with the CACNA1C promoter and other potential regulatory regions. Our results elucidate the pathogenic relevance of one of the best-supported risk loci for schizophrenia and bipolar disorder.

/pdf/functional-characterization-of-schizophrenia-associated-4pp25f4ahc.pdf

Rebecca Yang

Papers

Functional Characterization of Schizophrenia-Associated Variation in CACNA1C.