Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia.

Academic Article

Abstract

  • DYT1 dystonia is an inherited disease linked to mutation in the TOR1A gene encoding for the protein torsinA. Although the mechanism by which this genetic alteration leads to dystonia is unclear, multiple lines of clinical evidence suggest a link between dystonia and a reduced dopamine D2 receptor (D2R) availability. Based on this evidence, herein we carried out a comprehensive analysis of electrophysiological, behavioral and signaling correlates of D2R transmission in transgenic mice with the DYT1 dystonia mutation. Electrophysiological recordings from nigral dopaminergic neurons showed a normal responsiveness to D2-autoreceptor function. Conversely, postsynaptic D2R function in hMT mice was impaired, as suggested by the inability of a D2R agonist to re-establish normal corticostriatal synaptic plasticity and supported by the reduced sensitivity to haloperidol-induced catalepsy. Although an in situ hybridization analysis showed normal D1R and D2R mRNA expression levels in the striata of hMT mice, we found a significant decrease of D2R protein, coupled to a reduced ability of D2Rs to activate their cognate Go/i proteins. Of relevance, we found that pharmacological blockade of adenosine A2A receptors (A2ARs) fully restored the impairment of synaptic plasticity observed in hMT mice. Together, our findings demonstrate an important link between torsinA mutation and D2R dysfunction and suggest that A2AR antagonism is able to counteract the deficit in D2R-mediated transmission observed in mutant mice, opening new perspectives for the treatment of this movement disorder.
  • Published In

    Keywords

  • Adenosine A2 Receptor Antagonists, Animals, Central Nervous System Agents, Corpus Striatum, Disease Models, Animal, Dopamine, Dystonia, GTP-Binding Protein alpha Subunits, Gi-Go, Mice, Mice, Transgenic, Molecular Chaperones, Neural Pathways, Neuronal Plasticity, Neurons, RNA, Messenger, Receptor, Adenosine A2A, Receptors, Dopamine D1, Receptors, Dopamine D2, Substantia Nigra, Synaptic Transmission
  • Digital Object Identifier (doi)

    Author List

  • Napolitano F; Pasqualetti M; Usiello A; Santini E; Pacini G; Sciamanna G; Errico F; Tassone A; Di Dato V; Martella G
  • Start Page

  • 434
  • End Page

  • 445
  • Volume

  • 38
  • Issue

  • 3