TMEM16A ablation in cholinergic medial habenula neurons induces early-onset schizophrenia-like phenotypes in mice

Abstract

Schizophrenia is a heterogeneous psychiatric disorder that remains inadequately treated with current therapies. Developing appropriate animal models that reflect the broad spectrum of schizophrenia symptoms is crucial for advancing our understanding of the disease and identifying effective treatments. However, existing animal models often have limitations in fully recapitulating the diverse symptomatology observed in humans. Previously, we reported that mice with conditional ablation of TMEM16A (ANO1) in cholinergic neurons of the medial habenula (ANO1 cKO) exhibit behavioral patterns indicative of anxiety, reduced social motivation, and anhedonia. In the present study, we found that these mice display schizophrenia-like phenotypes, including impaired prepulse inhibition (PPI), enhanced cocaine sensitivity, and reduced c-Fos expression in the medial prefrontal cortex (mPFC), a feature also observed in patients with schizophrenia. Moreover, ANO1 cKO mice exhibited elevated Drd2 expression in the ventral medial geniculate nucleus (MGv) and transcriptomic alterations overlapping with schizophrenia-associated genes. Importantly, these phenotypes emerged only when ANO1 deletion occurred during development, whereas adult-stage manipulation failed to reproduce them, underscoring a critical developmental window for habenular–thalamocortical circuit maturation. This developmental specificity represents a central novelty of the model and provides new insight into how early-life dysregulation of habenular cholinergic signaling contributes to schizophrenia-related pathophysiology.