title: HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease.
abstract: Parkinson's disease is a common neurodegenerative disorder characterized by a profound motor disability that is traceable to the emergence of synchronous, rhythmic spiking in neurons of the external segment of the globus pallidus (GPe). The origins of this pathophysiology are poorly defined for the generation of pacemaking. After the induction of a parkinsonian state in mice, there was a progressive decline in autonomous GPe pacemaking, which normally serves to desynchronize activity. The loss was attributable to the downregulation of an ion channel that is essential in pacemaking, the hyperpolarization and cyclic nucleotide-gated (HCN) channel. Viral delivery of HCN2 subunits restored pacemaking and reduced burst spiking in GPe neurons. However, the motor disability induced by dopamine (DA) depletion was not reversed, suggesting that the loss of pacemaking was a consequence, rather than a cause, of key network pathophysiology, a conclusion that is consistent with the ability of L-type channel antagonists to attenuate silencing after DA depletion.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
authors.forename: C Savio
authors.initials: CS
authors.lastname: Chan
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Glajch
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Gertler
authors.forename: Jaime N
authors.initials: JN
authors.lastname: Guzman
authors.forename: Jeff N
authors.initials: JN
authors.lastname: Mercer
authors.forename: Alan S
authors.initials: AS
authors.lastname: Lewis
authors.forename: Alan B
authors.initials: AB
authors.lastname: Goldberg
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tkatch
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Shigemoto
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Fleming
authors.forename: Dane M
authors.initials: DM
authors.lastname: Chetkovich
authors.forename: Pavel
authors.initials: P
authors.lastname: Osten
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kita
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D053447:Channelopathies / Q000503:physiopathology*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015536:Down-Regulation; D005822:Genetic Vectors / Q000008:administration & dosage; D005917:Globus Pallidus / Q000503:physiopathology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000503:physiopathology*; D015221:Potassium Channels; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D016627:Oxidopamine; D002118:Calcium; D004298:Dopamine