Er81 transcription factor fine-tunes striatal cholinergic interneuron activity and drives habit formation

Abstract

The molecular mechanisms tuning cholinergic interneuron (CIN) activity, although crucial for striatal function and behavior, remain largely unexplored. Previous studies report that the Etv1/Er81 transcription factor is vital for regulating neuronal maturation and activity. While Er81 is known to be expressed in the striatum during development, its specific role in defining CIN properties and the resulting consequences on striatal function is unknown. We report here that Er81 is expressed in CINs and its specific ablation leads to prominent changes in their molecular, morphologic, and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further reveal that Er81 expression is required for normal CIN pause and time-locked responses to sensorimotor inputs in awake mice. Overall, this study uncovers a new cell type-specific control of CIN function in the striatum which drives habit formation in adult male mice.