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Title: SK channel function regulates the dopamine phenotype of neurons in the substantia nigra pars compacta
Authors: Aumann, T. D ×
Gantois, Ilse
Egan, K
Vais, A
Tomas, D
Drago, J
Horne, M. K #
Issue Date: Oct-2008
Publisher: Academic press inc elsevier science
Series Title: Experimental neurology vol:213 issue:2 pages:419-430
Abstract: 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.
URI: 
ISSN: 0014-4886
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Biological Psychology
× corresponding author
# (joint) last author

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