Chrna6, encoding the α6 subunit of nicotinic acetylcholine receptors (nAChR), is a crucial gene. nAChRs are ligand-gated ion channels, and Chrna6-containing nAChRs are involved in the cholinergic modulation of dopamine release in the striatum [3]. The CHRNB3-Chrna6 gene cluster on chromosome 8 is also significantly associated with nicotine dependence [1].

Functional studies in mice have shown that α6 *-nAChRs located in the ventral tegmental area (VTA) are important in controlling nicotine self-administration. Genetic knock-in strains have demonstrated that replacement of Leu with Ser in the 9' residue in the M2 domain of α6 produces nicotine-hypersensitive mice with enhanced dopamine release, indicating the role of Chrna6 in nicotine-induced reward and withdrawal [1]. In a chronic unpredictable mild stress (CUMS) induced major depressive disorder (MDD) rat model, inhibition of the Chrna6 ion channel ameliorated depression-like behavior, suggesting its potential involvement in MDD pathophysiology [2].

In conclusion, Chrna6 plays essential roles in cholinergic modulation, especially in dopamine release regulation and is associated with nicotine dependence and potentially MDD. Mouse models, including genetic manipulation and knock-in strains, have been valuable in revealing these functions, providing insights into the pathological processes related to nicotine addiction and MDD.

References:

1. Wen, L, Yang, Z, Cui, W, Li, M D. 2016. Crucial roles of the CHRNB3-CHRNA6 gene cluster on chromosome 8 in nicotine dependence: update and subjects for future research. In Translational psychiatry, 6, e843. doi:10.1038/tp.2016.103. https://pubmed.ncbi.nlm.nih.gov/27327258/

2. Kavuran Buran, İlay, Onalan Etem, Ebru, Tektemur, Ahmet. 2022. Inhibition of TRPC1, TRPM4 and CHRNA6 ion channels ameliorates depression-like behavior in rats. In Behavioural brain research, 423, 113765. doi:10.1016/j.bbr.2022.113765. https://pubmed.ncbi.nlm.nih.gov/35063497/

3. Martinelli, Simone, Cordeddu, Viviana, Galosi, Serena, Tartaglia, Marco, Leuzzi, Vincenzo. 2020. Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism. In Parkinsonism & related disorders, 72, 75-79. doi:10.1016/j.parkreldis.2020.02.003. https://pubmed.ncbi.nlm.nih.gov/32120303/