Kv1.3 is a candidate target to prevent the hypercholinergic state of parkinsonism.

TUBERT C; TARAVINI IR; PROST A; SANCHEZ G; MURER MG; RELA L

Mar del Plata

Congreso; XXX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencia.; 2015

Sociedad Argentina de Investigación en Neurociencia

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. The main source of striatal Ach is a small group of striatal cholinergic interneurons (ChIs). Previously we found that ChIs are hyperexcitable in a rat model of PD as a result of a lack of accommodation. Our aim is to identify currents that regulate ChI accommodation in mouse brain slices. Margatoxin (MgTx), a blocker of Kv1.3 channels, markedly attenuated accommodation in ChIs, as shown by an increase in the number of spikes (p=0.003) and a prolonged firing (p=0.008) during a depolarizing current step. MgTx also increased spontaneous firing (p=0.0455). We have isolated and characterized the MgTx-sensitive current (Imax=1500 pA). Immunohistochemistry in brain sections and PCR of laser dissected ChIs revealed the expression of Kv1.3 channels. Thus, ChIs express a functionally relevant Kv1 conductance. Then we evaluated the influence of endogenous DA on accommodation. Confirming previous findings, fewer ChIs show accommodation in a mouse model of PD induced with 6-OHDA. This hyperexcitability is associated to smaller MgTx-sensitive currents in ChIs of 6-OHDA-lesioned mice compared to sham-mice (p