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

CECILIA TUBERT; IRENE TARAVINI; ALEJANDRA PROST; GONZALO SANCHEZ; MARIO GUSTAVO MURER; LORENA RELA

Mar del Plata

Congreso; XXX Reunion Anual; 2015

Sociedad Argentina de Investigacion en Neurociencias

Balanced actions of dopamine (DA) and Acetylcholine (ACh) shape striatal function. InParkinson´s disease (PD) this balance is lost, leading to a hypercholinergic state. The mainsource of striatal Ach is a small group of striatal cholinergic interneurons (ChIs). Previouslywe 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 inmouse brain slices. Margatoxin (MgTx), a blocker of Kv1.3 channels, markedly attenuatedaccommodation in ChIs, as shown by an increase in the number of spikes (p=0.003) and aprolonged firing (p=0.008) during a depolarizing current step. MgTx also increasedspontaneous firing (p=0.0455). We have isolated and characterized the MgTx-sensitivecurrent (Imax=1500 pA). Immunohistochemistry in brain sections and PCR of laserdissected ChIs revealed the expression of Kv1.3 channels. Thus, ChIs express a functionallyrelevant Kv1 conductance. Then we evaluated the influence of endogenous DA onaccommodation. Confirming previous findings, fewer ChIs show accommodation in amouse model of PD induced with 6-OHDA. This hyperexcitability is associated to smallerMgTx-sensitive currents in ChIs of 6-OHDA-lesioned mice compared to sham-mice(p