Recurrent implication of striatal cholinergic interneurons in a range of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders

Cholinergic interneurons are “gatekeepers” for striatal circuitry and play pivotal roles in attention, goal-directed actions, habit formation, and behavioral flexibility. Accordingly, pertur-bations to striatal cholinergic interneurons have been associated with many neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The role of acetylcholine in many of these disorders is well known, but the use of drugs targeting cholinergic systems fell out of favor due to adverse side effects and the introduction of other broadly acting compounds. However, in response to recent findings, re-examining the mechanisms of cholinergic interneuron dysfunction may reveal key insights into underlying pathogeneses. Here, we provide an update on striatal cholinergic interneuron function, connectivity, and their putative involvement in several disorders. In doing so, we aim to spotlight recurring physiological themes, circuits, and mechanisms that can be investigated in future studies using new tools and approaches.