Activation of D1R reduces the Kv1.3 current and contributes to the hypercholinergic state of parkinsonism

GUSTAVO MURER; PAZ, RODRIGO MANUEL; CECILIA TUBERT

Villa Carlos Paz, Córdoba

Congreso; XXXIV Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2019

XXXIV Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias

Balanced actions of dopamine (DA) and acetylcholine (ACh) shape striatal function. In Parkinson?s disease (PD) this balance is lost, leading to a hypercholinergic state. Striatal cholinergic interneurons (ChIs) are the main source of striatal ACh. Previously we found that ChIs are hyperexcitable in a mouse model of PD as a result of a reduction in a current mediated by Kv1.3 channels, which is not explained by reduced channel expression. Our aim is to identify the mechanisms that underlie this hyperexcitability. With ex-vivo electrophysiological recordings, we found that SKF81297 (SKF), a DA D1-type receptor (D1R) agonist, increases the excitability of ChIs, and this effect is occluded by Margatoxin (MgTx), a blocker of Kv1.3 channels. The reduction in the current after application of SKF is also occluded by MgTx, suggesting a shared signaling pathway. Preliminary results suggest that this common pathway is adenylatecyclase (AC) dependent, since activating it with Fosrkolin increases the excitability and reduces the current in ChIs in the same way as SKF and MgTx do, and either of the effects are occluded by them. Our results suggest that the activation of D1R promotes the activation of the AC and, probably through PKA, induces the reduction of the Kv1.3 current and the subsequent hyperexcitability of ChIs. Further experiments in a mouse model of PD will be necessary to evaluate if an alteration of this pathway produces the ChIs hyperexcitability observed in this condition.