کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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6019482 | 1186561 | 2008 | 12 صفحه PDF | دانلود رایگان |
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 THâ 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 THâ and TH+ cells during recovery from 6-OHDA in mice. Three distinct phenotypes were observed: (1) THâ 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 THâ 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 THâ and chronic (2Â weeks) inhibition of SK channel function in normal mice shifted the neurochemical phenotype of SNc from TH+ to THâ (i.e. decreased TH+ and increased THâ cell numbers). Importantly, chronic facilitation of SK channel function shifted the neurochemical phenotype of SNc from THâ to TH+ (i.e. increased TH+ and decreased THâ 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.
Journal: Experimental Neurology - Volume 213, Issue 2, October 2008, Pages 419-430