Synchronous activation of striatal cholinergic interneurons induces local serotonin release

Striatal cholinergic interneurons (CINs) can drive local dopamine release via nicotinic acetylcholine receptors (nAChRs) expressed on dopaminergic axons, but their role in modulating serotonin (5-HT) signaling is poorly understood. Here, we show that synchronous activation of CINs directly triggers local 5-HT release in the dorsal striatum via nAChRs expressed on serotonergic axons. This CIN–5-HT coupling is not detectable in the ventral striatum, despite its substantially denser serotonergic innervation. The nAChR-dependent release not only increases 5-HT levels in the dorsal striatum, but also expands the spatial footprint of serotonergic signaling. In Sapap3-/- mice, a model of obsessive-compulsive disorder (OCD)-like behavior, this mechanism is exaggerated due to a hypercholinergic state, selectively amplifying the nAChR-dependent component of monoamine release. These findings demonstrate a regionally confined form of acetylcholine–5-HT crosstalk in the striatum and identify CINs as regulators of 5-HT dynamics in both healthy and pathological states. Neural mechanisms underlying local striatal serotonin release are not fully understood. Here authors show that striatal cholinergic interneurons drive local serotonin release by activating nicotinic receptors on serotonergic axons in the dorsal but not ventral striatum. This mechanism expands the spatial range of serotonin release and is exaggerated in a mouse model of compulsive behavior.