Cholinergic dysfunction alters synaptic integration between thalamostriatal and corticostriatal inputs in DYT1 dystonia

J Neurosci. 2012 Aug 29;32(35):11991-2004. doi: 10.1523/JNEUROSCI.0041-12.2012.

Abstract

Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M(1) and M(2) muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M(1) muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time window for synaptic integration between thalamostriatal and corticostriatal inputs, which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements.

Publication types

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

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Cholinergic Neurons / pathology*
  • Corpus Striatum / physiology*
  • Dystonia / genetics*
  • Dystonia / physiopathology
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Chaperones / genetics*
  • Mutation / genetics
  • Neural Pathways / pathology
  • Synapses / pathology*
  • Thalamus / physiology*
  • Time Factors

Substances

  • Dyt1 protein, mouse
  • Molecular Chaperones