SK channel function regulates the dopamine phenotype of neurons in the substantia nigra pars compacta

Parkinson's disease (PD) is characterized by loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta(SNc). It is widely believed that replacing lost SNc DA neurons is a key to longer-term effective treatment of PD motor symptoms, but generating new SNc DA neurons in PD patients has proven difficult. Following loss of tyrosine hydroxylase-positive (TH+) SNc neurons in the rodent 6-hydroxy-DA (6-OHDA) model of PD, the number of TH+ neurons partially recovers and there is evidence this occurs via phenotype "shift" from TH- to TH+ cells. Understanding how this putative phenotype shift occurs may help increase SNc DAergic neurons in PD patients. In this study we characterize the electrophysiology of SNc TH- and TH+ cells during recovery from 6-OHDA in mice. Three distinct phenotypes were observed: (1) TH- were fast discharging with a short duration action potential (AP), short afterhyperpolarization (AHP) and no small conductance Ca2+-activated K+ (SK) current; (2) TH+ were slow discharging with a long AP, long AHP and prominent SK Current; and (3) cells with features "intermediate" between these TH- and TH+ phenotypes. The same 3 phenotypes were present also in the normal and D2 DA receptor knock-out SNc suggesting they are more closely related to the biology of TH expression than recovery from 6-OHDA. Acute inhibition of SK channel function shifted the electrophysiological phenotype of TH+ neurons toward TH- and chronic (2 weeks) inhibition of SK channel function in normal mice shifted the neurochemical phenotype of SNc from TH+ to TH- (i.e. decreased TH+ and increased TH- cell numbers). Importantly, chronic facilitation of SK channel function shifted the neurochemical phenotype of SNc from TH- to TH+ (i.e. increased TH+ and decreased TH- cell numbers). We conclude that SK channel function bidirectionally regulates the DA phenotype of SNc cells and facilitation of SK channels may be a novel way to increase the number of SNc DAergic neurons in PD patients. Crown Copyright (c) 2008 Published by Elsevier Inc. All rights reserved.