Serotonin inhibits low-threshold spike interneurons in the striatum

Low-threshold spike interneurons (LTSIs) are important elements of the striatal architecture and the only known source of nitric oxide in this nucleus, but their rarity has so far prevented systematic studies. Here, we used transgenicmice in which green fluorescent protein is expressed under control of the neuropeptide Y (NPY) promoter and striatal NPY-expressing LTSIs can be easily identified, to investigate the effects of serotonin on these neurons. In sharp contrast with its excitatory action on other striatal interneurons, serotonin ( 30 mu M) strongly inhibited LTSIs, reducing or abolishing their spontaneous firing activity and causing membrane hyper-polarisations. These hyperpolarisations persisted in the presence of tetrodotoxin, were mimicked by 5-HT2C receptor agonists and reversed by 5-HT2C antagonists. Voltage- clamp slow-ramp experiments showed that serotonin caused a strong increase in an outward current activated by depolarisations that was blocked by the specific Mcurrent blocker XE 991. In current-clamp experiments, XE 991 per se causedmembrane depolarisations in LTSIs and subsequent application of serotonin ( in the presence of XE 991) failed to affect these neurons. We concluded that serotonin strongly inhibits striatal LTSIs acting through postsynaptic 5-HT2C receptors and increasing an Mtype current.