SEROTONIN AND SEROTONERGIC INPUTS MODULATE CHOLINERGIC INTERNEURONS IN THE STRIATUM ON DIFFERENT TIMESCALES

The striatum, the major input hub of the basal ganglia, integrates converging glutamatergic and GABAergic inputs from cortical and subcortical regions, along with modulatory dopaminergic signals from the midbrain that are critical for motor initiation, learning, and reward. In addition, approximately one-third of serotonergic neurons in the dorsal raphe nucleus project to the striatum, yet the influence of serotonin on striatal circuits remains less well understood. Here, we examined how serotonin and serotonergic inputs affect striatal cholinergic interneurons (ChINs). ChINs regulate action selection and reinforcement signalling by exerting inhibitory control over medium spiny neurons and are interconnected through polysynaptic pathways, enabling widespread coordination across the striatum. Using paired whole-cell recordings combined with pharmacological manipulations, we found that serotonin modulates ChIN intrinsic excitability and suppresses polysynaptic inhibitory interactions between them via 5-HT2 receptors. Furthermore, optogenetic activation of striatal serotonergic fibres revealed a fast, monosynaptic glutamatergic input onto ChINs. Together, these findings identify previously unrecognized mechanisms by which serotonin and serotonergic projections modulate ChIN networks, highlighting the intricate interplay between acetylcholine, dopamine, and serotonin in shaping striatal function. Given the broad influence of ChIN activity, serotonergic modulation likely has widespread consequences for striatal circuits and may provide insight into the mechanisms underlying non-motor symptoms of Parkinson’s disease.