Anoctamin 2 deletion alters dopamine-related signaling and impairs inhibitory behavioral control in mice.

Anoctamin 2 (ANO2, TMEM16B) is a calcium-activated chloride channel best known for its role in sensory neurons, yet its expression in multiple brain regions associated with dopamine-related signaling, including the prefrontal cortex, striatum, substantia nigra, ventral tegmental area, and cerebellum, suggests broader functions in central neural circuits. However, the contribution of ANO2 to dopamine-related neural function and behavior remains undefined. To address this question, we generated ANO2-deficient mice using CRISPR-Cas9-mediated gene editing and examined their behavioral and neurochemical phenotypes. ANO2 knockout mice exhibited age-dependent hyperactivity, impaired inhibitory behavioral control, altered aversive/risk-related responses, and selective motor coordination deficits, while spatial learning and memory were preserved. Neurochemically, ANO2 deficiency resulted in reduced tyrosine hydroxylase expression and phosphorylation, decreased dopamine levels despite unchanged dopamine transporter expression, region- and subtype-dependent dopamine receptor alterations, and reduced downstream signaling markers across cortico-striatal and cerebellar circuits. These changes suggest impaired dopamine biosynthesis and altered dopamine-related signaling rather than broad disruption of dopaminergic neuronal identity. Together, these findings identify ANO2 as a potential modulator of dopamine-related signaling and inhibitory behavioral control, expanding current understanding of calcium-activated chloride channel function in neural circuits relevant to behavioral domains implicated in neuropsychiatric disorders.