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

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.
AuthorsFrancesco Napolitano, Massimo Pasqualetti, Alessandro Usiello, Emanuela Santini, Giulia Pacini, Giuseppe Sciamanna, Francesco Errico, Annalisa Tassone, Valeria Di Dato, Giuseppina Martella, Dario Cuomo, Gilberto Fisone, Giorgio Bernardi, Georgia Mandolesi, Nicola B Mercuri, David G Standaert, Antonio Pisani
JournalNeurobiology of disease (Neurobiol Dis) Vol. 38 Issue 3 Pg. 434-45 (Jun 2010) ISSN: 1095-953X [Electronic] United States
PMID20227500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Adenosine A2 Receptor Antagonists
  • Central Nervous System Agents
  • Dyt1 protein, mouse
  • Molecular Chaperones
  • RNA, Messenger
  • Receptor, Adenosine A2A
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Dopamine
Topics
  • Adenosine A2 Receptor Antagonists
  • Animals
  • Central Nervous System Agents (pharmacology)
  • Corpus Striatum (drug effects, physiopathology)
  • Disease Models, Animal
  • Dopamine (metabolism)
  • Dystonia (drug therapy, genetics, physiopathology)
  • GTP-Binding Protein alpha Subunits, Gi-Go (metabolism)
  • Mice
  • Mice, Transgenic
  • Molecular Chaperones (genetics, metabolism)
  • Neural Pathways (drug effects, physiopathology)
  • Neuronal Plasticity (drug effects, physiology)
  • Neurons (drug effects, physiology)
  • RNA, Messenger (metabolism)
  • Receptor, Adenosine A2A (metabolism)
  • Receptors, Dopamine D1 (metabolism)
  • Receptors, Dopamine D2 (metabolism)
  • Substantia Nigra (drug effects, physiopathology)
  • Synaptic Transmission (drug effects, physiology)

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