Dopamine depletion induced up-regulation of HCN3 enhances rebound excitability of basal ganglia output neurons

Neurobiol Dis. 2009 Apr;34(1):178-88. doi: 10.1016/j.nbd.2009.01.007.

Abstract

Motor symptoms in Parkinson's disease (PD) are associated with complex changes of firing properties in basal ganglia output neurons (BGON). The abnormalities are generally attributed to altered synaptic input and potential post-synaptic mechanisms are currently unknown. Our cell-type selective transcriptome analyses of BGON in the rat 6-hydroxydopamine (6-OHDA) model of PD identified the ion channel HCN3 as a likely contributor to altered neuronal excitability. Quantitative PCR experiments confirmed the HCN3 upregulation in the rat and mouse 6-OHDA models and also demonstrated selectivity of the effect for HCN3. In accordance with the mRNA expression data, in vitro whole cell patch-clamp recordings in BGON showed increased HCN3 current amplitudes and increased rebound excitability in BGON of 6-OHDA treated rats. These data establish HCN3 up-regulation as a novel candidate mechanism that might contribute to the in vivo changes of electrical activity in basal ganglia output neurons of the parkinsonian brain.

Publication types

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

MeSH terms

  • Animals
  • Basal Ganglia / physiopathology*
  • Cyclic Nucleotide-Gated Cation Channels / antagonists & inhibitors
  • Cyclic Nucleotide-Gated Cation Channels / metabolism*
  • Disease Models, Animal
  • Dopamine / deficiency*
  • Gene Expression
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Male
  • Membrane Potentials
  • Mice
  • Mice, Inbred C57BL
  • Neurons / physiology*
  • Oxidopamine
  • Parkinsonian Disorders / physiopathology*
  • Potassium Channels / metabolism*
  • Pyrimidines / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation

Substances

  • Cyclic Nucleotide-Gated Cation Channels
  • HCN3 protein, mouse
  • HCN3 protein, rat
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Potassium Channels
  • Pyrimidines
  • RNA, Messenger
  • ICI D2788
  • Oxidopamine
  • Dopamine