Genetic deletion of Rhes or pharmacological blockade of mTORC1 prevent striato-nigral neurons activation in levodopa-induced dyskinesia

Neurobiol Dis. 2016 Jan;85:155-163. doi: 10.1016/j.nbd.2015.10.020. Epub 2015 Oct 29.

Abstract

Ras homolog enriched in striatum (Rhes) is a small GTP-binding protein that modulates signal transduction at dopamine receptors, and also activates mammalian target of rapamycin complex 1 (mTORC1). Rhes binding to mTORC1 is hypothesized to play a role in motor disorders such as levodopa-induced dyskinesia. Here, we investigate the behavioral and in vivo neurocircuitry changes associated with genetic deletion of Rhes or inhibition of mTORC1 signaling in the mouse model of levodopa-induced dyskinesia. 6-Hydroxydopamine-hemilesioned Rhes knockout mice and wild-type littermates were chronically treated with levodopa. In parallel, 6-hydroxydopamine-hemilesioned naïve mice were chronically treated with levodopa or levodopa plus rapamycin, to block mTORC1 pathway activation. Dyskinetic movements were monitored during levodopa treatment along with motor activity on the rotarod. Finally, dyskinetic mice underwent microdialysis probe implantation in the dopamine-depleted striatum and ipsilateral substantia nigra reticulata, and GABA and glutamate levels were monitored upon acute challenge with levodopa. Both Rhes knockouts and rapamycin-treated mice developed less dyskinesia than controls, although only rapamycin-treated mice fully preserved rotarod performance on levodopa. Levodopa elevated nigral GABA and glutamate in controls but not in Rhes knockouts or rapamycin-treated mice. Levodopa also stimulated striatal glutamate in controls and Rhes knockouts but not in rapamycin-treated mice. We conclude that both genetic deletion of Rhes and pharmacological blockade of mTORC1 significantly attenuate dyskinesia development by reducing the sensitization of striato-nigral medium-sized spiny neurons to levodopa. However, mTORC1 blockade seems to provide a more favorable behavioral outcome and a wider effect on neurochemical correlates of dyskinesia.

Keywords: 6-Hydroxydopamine; Dyskinesia; GABA; Glutamate; Levodopa; Microdialysis; Parkinson's disease; Rapamycin; Rhes; mTORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / toxicity*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Disease Models, Animal
  • Dyskinesia, Drug-Induced / drug therapy*
  • Dyskinesia, Drug-Induced / metabolism*
  • Dyskinesia, Drug-Induced / pathology
  • Female
  • GTP-Binding Proteins / deficiency*
  • GTP-Binding Proteins / genetics
  • Glutamic Acid / metabolism
  • Levodopa / toxicity*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology
  • Sirolimus / pharmacology
  • Substantia Nigra / drug effects
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antiparkinson Agents
  • Multiprotein Complexes
  • Neuroprotective Agents
  • Glutamic Acid
  • Levodopa
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • GTP-Binding Proteins
  • Rasd2 protein, mouse
  • Sirolimus