HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease

Nat Neurosci. 2011 Jan;14(1):85-92. doi: 10.1038/nn.2692. Epub 2010 Nov 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Channelopathies / physiopathology*
  • Dependovirus / genetics
  • Disease Models, Animal
  • Dopamine / metabolism
  • Down-Regulation
  • Genetic Vectors / administration & dosage
  • Globus Pallidus / physiopathology*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / genetics
  • Ion Channels / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microinjections
  • Neurons / metabolism
  • Neurons / physiology*
  • Oxidopamine
  • Parkinson Disease / physiopathology*
  • Potassium Channels
  • Substantia Nigra / metabolism

Substances

  • Hcn2 protein, mouse
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Potassium Channels
  • Oxidopamine
  • Calcium
  • Dopamine