M2 cortex-dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's disease

Elife. 2020 Oct 5:9:e57017. doi: 10.7554/eLife.57017.

Abstract

Huntington's disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD.

Keywords: basal ganglia; cortico-striatal; long-term depression; motor behaviour; mouse; neuroscience; optogenetics; striatum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebral Cortex* / cytology
  • Cerebral Cortex* / physiology
  • Cerebral Cortex* / radiation effects
  • Corpus Striatum* / cytology
  • Corpus Striatum* / physiology
  • Corpus Striatum* / radiation effects
  • Electric Stimulation*
  • Glutamic Acid / metabolism
  • Huntington Disease / physiopathology*
  • Mice
  • Motor Activity / physiology
  • Neuronal Plasticity / physiology
  • Neurons / metabolism
  • Neurons / physiology
  • Optogenetics

Substances

  • Glutamic Acid