D1/D5 Inverse Agonists Restore Striatal Cholinergic Interneuron Physiology in Dyskinetic Mice

ABSTRACT Background In advanced stages of Parkinson's disease (PD), dyskinesia and motor fluctuations become seriously debilitating and therapeutic options become scarce. Aberrant activity of striatal cholinergic interneurons (SCIN) has been shown to be critical to PD and dyskinesia, but the systemic administration of cholinergic medications can exacerbate extrastriatal‐related symptoms. Thus, targeting the mechanisms causing pathological SCIN activity in severe PD with motor fluctuations and dyskinesia is a promising therapeutic alternative. Methods We used ex vivo electrophysiological recordings combined with pharmacology to study the alterations in intracellular signaling that contribute to the altered SCIN physiology observed in the 6‐hydroxydopamine mouse model of PD treated with levodopa. Results The altered phenotypes of SCIN of parkinsonian mice during the “off levodopa” state resulting from aberrant Kir/leak and Kv1.3 currents can be rapidly reverted by acute inhibition of cAMP‐ERK1/2 signaling. Inverse agonists that inhibit the ligand‐independent activity of D5 receptors, like clozapine, restore Kv1.3 and Kir/leak currents and SCIN normal physiology in dyskinetic mice. Conclusion Our work unravels a signaling pathway involved in the dysregulation of membrane currents causing SCIN hyperexcitability and burst‐pause activity in parkinsonian mice treated with levodopa (l‐dopa). These changes persist during off‐medication periods due to tonic mechanisms that can be acutely reversed by pharmacological interventions. Thus, targeting the D5‐cAMP‐ERK1/2 signaling pathway selectively in SCIN may have therapeutic effects in PD and dyskinesia by restoring the normal SCIN function. © 2022 International Parkinson and Movement Disorder Society.