STRIATAL CHOLINERGIC INTERNEURON PAUSE RESPONSE: INTRINSICALLY GENERATED BY KV1.3 CURRENT ACTIVATION AND REGULATED BY D5R

TUBERT, CECILIA; PAZ, RODRIGO MANUEL; MURER, MARIO GUSTAVO

Buenos Aires

Congreso; Frontiers in Bioscience 4; 2023

Striatal cholinergic interneurons (SCIN) are the main source of striatal acetylcholine. SCIN are, presumably, the tonically-active neurons that show a pause response to reward-related stimuli, important for striatum-dependent learning, which is lost in parkinsonian animals. The gold standard Parkinson’s disease (PD) therapy is L-dopa administration, but prolonged treatment may result in dyskinesia. Many studies show that the striatal circuit changes after a prolonged L-dopa treatment, but how these changes affect the pause response of SCIN remains unknown. Moreover, the nature of the pause remains controversial: both dopamine and thalamic input to SCIN are necessary, but how they trigger the pause isn’t clear. Our aim is to identify the mechanisms that underlie this response and study their alteration in PD and after L-dopa treatment. Previously, we found that SCIN become hyperexcitable in parkinsonian and dyskinetic mice due to an increased ligand-independent activity of D5 receptors (D5R), which reduces the Kv1 current and increases SCIN excitability. Here, we perform ex-vivo cell-attached recordings of mouse SCIN and optogenetically activate their thalamic afferents. In normal conditions, this generates a pause that disappears when D5R are selectively stimulated or when Kv1.3 channels are blocked. Surprisingly, we have found that the pause is absent in SCIN from mice in the OFF state of an L-dopa treatment and preliminary results suggest that it is reinstated when the D5R ligand-independent activity is reduced with the inverse agonist clozapine. These results suggest that the pause is generated by intrinsic activation of Kv1.3 current in response to depolarization induced by thalamic afferents and regulated by D5R. In parkinsonian mice treated with L-dopa, a D5R-Kv1 altered pathway may contribute to the absence of the pause. They also suggest new strategies for restoring the pause that may prove beneficial in dyskinesia.