Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia

Neurobiol Dis. 2006 Nov;24(2):318-25. doi: 10.1016/j.nbd.2006.07.006. Epub 2006 Aug 28.

Abstract

Early-onset torsion dystonia (DYT1) is an autosomal dominant disease caused by a deletion in the gene encoding the protein torsinA. Recently, a transgenic mouse model of DYT1 has been described, expressing either the human wild-type torsinA (hWT) or mutant torsinA (hMT). We recorded the activity of striatal cholinergic interneurons of hWT, hMT, and control mice. In slice preparations, no significant differences were observed in resting membrane potential (RMP), firing activity, action potential duration or Ih current. Quinpirole, a D2-like dopamine receptor agonist, did not produce detectable effects on RMP of cholinergic interneurons in control mice and hWT mice, but in the hMT mice caused membrane depolarization and an increase in the firing rate. D2 receptor activation inhibits N-type high-voltage-activated calcium currents. We found that, in isolated interneurons from hMT mice, the quinpirole-mediated inhibition of N-type currents was significantly larger than in hWT and controls. Moreover, the N-type component was significantly over-represented in hMT mice. The altered sensitivity of N-type channels in hMT mice could account for the paradoxical excitatory effect of D2 stimulation. Our data support the existence of an imbalance between striatal dopaminergic and cholinergic signaling in DYT1 dystonia.

Publication types

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

MeSH terms

  • Acetylcholine / metabolism
  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, N-Type / drug effects
  • Calcium Channels, N-Type / metabolism*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Corpus Striatum / physiopathology
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopamine Agonists / pharmacology
  • Dystonia Musculorum Deformans / genetics
  • Dystonia Musculorum Deformans / metabolism*
  • Dystonia Musculorum Deformans / physiopathology
  • Humans
  • Interneurons / drug effects
  • Interneurons / metabolism*
  • Mice
  • Mice, Transgenic
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*

Substances

  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Dopamine Agonists
  • Molecular Chaperones
  • Receptors, Dopamine D2
  • TOR1A protein, human
  • Acetylcholine
  • Dopamine