title: SK channel function regulates the dopamine phenotype of neurons in the substantia nigra pars compacta.
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 Ca(2+)-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.
authors.affiliation: Howard Florey Institute, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: T D
authors.initials: TD
authors.lastname: Aumann
authors.forename: I
authors.initials: I
authors.lastname: Gantois
authors.forename: K
authors.initials: K
authors.lastname: Egan
authors.forename: A
authors.initials: A
authors.lastname: Vais
authors.forename: D
authors.initials: D
authors.lastname: Tomas
authors.forename: J
authors.initials: J
authors.lastname: Drago
authors.forename: M K
authors.initials: MK
authors.lastname: Horne
mesh_terms: D000818:Animals; D004298:Dopamine / Q000032:analysis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000737:chemistry / Q000502:physiology*; D010641:Phenotype; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000032:analysis / Q000502:physiology*; D013378:Substantia Nigra / Q000737:chemistry / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000502:physiology
chemical_list: D051640:Small-Conductance Calcium-Activated Potassium Channels; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine