Cacna1c-KO Mouse

CACNA1C encodes the pore-forming subunit of the CaV1.2 L-type Ca2+ channel, a crucial component in membrane physiology across multiple tissues like the heart, brain, and immune system [1]. This channel is involved in various cellular functions related to calcium ion transmembrane processes. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable in studying its function.

Mutations in CACNA1C are associated with a wide range of disorders. Timothy syndrome (TS), a severe multisystem disorder with neurodevelopmental deficits, long-QT syndrome, cardiac arrhythmias, craniofacial abnormalities, and immune deficits, was the first disorder linked to CACNA1C mutations [1]. Heterozygous variants can also cause isolated neurological manifestations like developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy [2]. Functional studies of missense variants via patch-clamp experiments demonstrated differential effects on channel function in vitro, including loss of function, neutral effect, and gain of function [2]. Large-scale genome-wide association studies have shown that genetic variation in CACNA1C increases the risk for psychiatric disorders, and its reduced gene dosage impacts adult hippocampal neurogenesis [3]. Meta-analysis indicates that CACNA1C (rs1006737) may be a susceptibility gene for schizophrenia [4]. Pharmacoepidemiological evidence suggests that calcium channel blockers targeting L-type calcium channels (LTCCs) encoded by CACNA1C might have beneficial effects on psychiatric disorders [5]. In Cacna1c± male rats, distinct brain activation patterns occur after appetitive extinction and renewal despite preserved behavioral responses [6].

In conclusion, CACNA1C is essential for membrane physiology in multiple tissues. Model-based research, especially through KO/CKO mouse models, has revealed its significant roles in various disease conditions, including neurological and psychiatric disorders. Understanding CACNA1C function provides insights into the mechanisms of these diseases, potentially guiding new treatment strategies.

References:

1. Herold, Kevin G, Hussey, John W, Dick, Ivy E. . CACNA1C-Related Channelopathies. In Handbook of experimental pharmacology, 279, 159-181. doi:10.1007/164_2022_624. https://pubmed.ncbi.nlm.nih.gov/36598608/

2. Rodan, Lance H, Spillmann, Rebecca C, Kurata, Harley T, Au, Ping Yee Billie, Shashi, Vandana. 2021. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations. In Genetics in medicine : official journal of the American College of Medical Genetics, 23, 1922-1932. doi:10.1038/s41436-021-01232-8. https://pubmed.ncbi.nlm.nih.gov/34163037/

3. Moon, Anna L, Haan, Niels, Wilkinson, Lawrence S, Thomas, Kerrie L, Hall, Jeremy. . CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis. In Schizophrenia bulletin, 44, 958-965. doi:10.1093/schbul/sby096. https://pubmed.ncbi.nlm.nih.gov/29982775/

4. Zhu, Dongjian, Yin, Jingwen, Liang, Chunmei, Wang, Yajun, Ma, Guoda. 2019. CACNA1C (rs1006737) may be a susceptibility gene for schizophrenia: An updated meta-analysis. In Brain and behavior, 9, e01292. doi:10.1002/brb3.1292. https://pubmed.ncbi.nlm.nih.gov/31033230/

5. Harrison, Paul J, Husain, Syed M, Lee, Hami, Haerty, Wilfried, Tunbridge, Elizabeth M. 2022. CACNA1C (CaV1.2) and other L-type calcium channels in the pathophysiology and treatment of psychiatric disorders: Advances from functional genomics and pharmacoepidemiology. In Neuropharmacology, 220, 109262. doi:10.1016/j.neuropharm.2022.109262. https://pubmed.ncbi.nlm.nih.gov/36154842/

6. Gasalla, Patricia, Manahan-Vaughan, Denise, Dwyer, Dominic Michael, Hall, Jeremy, Méndez-Couz, Marta. 2023. Characterisation of the neural basis underlying appetitive extinction & renewal in Cacna1c rats. In Neuropharmacology, 227, 109444. doi:10.1016/j.neuropharm.2023.109444. https://pubmed.ncbi.nlm.nih.gov/36724867/