Dopaminergic Modulation of Striatal Somatostatin Interneurons Shapes Motor Learning and L-DOPA-Induced Dyskinesia.

Somatostatin-expressing low-threshold spiking interneurons (SOM-INs) constitute a key inhibitory population in the dorsal striatum, yet their contribution to parkinsonian states and L-DOPA-induced dyskinesia (LID) remains poorly understood. Here, we combined in vivo behavioral assays, chemogenetics, and ex vivo electrophysiology to examine how nigrostriatal dopamine loss and dopaminergic therapy shape SOM-INs' activity and function. During LID, SOM-INs displayed increased c-Fos expression, revealing their recruitment during dyskinetic states. Patch-clamp recordings showed that SOM-INs in control mice fire tonically with characteristic abrupt pauses. While their firing patterns are preserved after dopamine depletion and L-DOPA therapy, dopamine depletion shifted their interspike interval distribution toward longer intervals, indicating reduced intrinsic activity. This deficit was partially reversed by chronic L-DOPA. Consistent with their expression of Drd1/Drd5 transcripts, SOM-INs were excited by the D1/D5 receptor agonist SKF81297 across groups. Chemogenetic inhibition experiments revealed a functional role for SOM-INs in early rotarod learning, demonstrating their contribution to motor skill acquisition, but did not affect baseline motor output in sham or parkinsonian mice. Moreover, SOM-IN inhibition during chronic L-DOPA treatment modestly but consistently exacerbated LID expression selectively during the wearing-off phase, without altering parkinsonian symptoms or the therapeutic efficacy of L-DOPA. Notably, SOM-IN inhibition did not modify the long-duration antiparkinsonian response that persisted after discontinuing L-DOPA. Together, these findings identify SOM-INs as an intrinsically active striatal interneuron population whose excitability is shaped by dopamine depletion and dopamine receptor stimulation, and whose activity restrains dyskinetic responses to dopaminergic overstimulation. Their selective influence on dyskinesia, but not on the therapeutic actions of L-DOPA, highlights SOM-INs as a potential target for circuit-level interventions aimed at improving the motor side-effect profile of dopaminergic therapies.