Striatal cholinergic interneuron pause response requires Kv1 channels, is absent in dyskinetic mice, and is restored by dopamine D5 receptor inverse agonism

Abstract

AbstractStriatal cholinergic interneurons (SCIN) exhibit pause responses conveying information about rewarding events, but the mechanisms underlying them remain elusive. Thalamic inputs induce a pause mediated by intrinsic mechanisms and regulated by dopamine D2 receptors, though the underlying membrane currents are unknown. Moreover, the role of D5 receptors (D5R) has not been addressed so far. We show that glutamate released by thalamic inputs in the dorsolateral striatum induces a burst in SCIN, followed by the activation of a Kv1-dependent delayed rectifier current responsible for the pause. Endogenous dopamine promotes the pause through D2R stimulation, while pharmacological stimulation of D5R suppresses it. Remarkably, the pause response is absent in parkinsonian mice rendered dyskinetic by chronic L-DOPA treatment but can be reinstated acutely by the inverse D5R agonist clozapine. Blocking the Kv1 current eliminates the pause reinstated by the D5R inverse agonist. In conclusion, the pause response is mediated by delayed rectifier Kv1 channels, which are tonically blocked in dyskinetic mice by a mechanism depending on D5R ligand-independent activity. Targeting these alterations may have therapeutic value in Parkinson’s disease.HighlightsThalamostriatal input triggers a burst followed by a pause in SCIN.Kv1, but not Kv7 or Kir2.2 channels, are necessary for the expression of the pause.D2R stimulation promotes, and D5R stimulation inhibits the pause.Thalamic bursts are not followed by a pause in SCIN from dyskinetic mice.D5R inverse agonism restores a Kv1-dependent pause response in dyskinetic mice.