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

Francesco 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

Research output: Contribution to journalArticle

58 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)434-445
Number of pages12
JournalNeurobiology of Disease
Volume38
Issue number3
DOIs
Publication statusPublished - Jun 2010

Fingerprint

Adenosine A2A Receptors
Dopamine D2 Receptors
Dystonia
Neuronal Plasticity
Mutation
Catalepsy
Autoreceptors
Proteins
Dopaminergic Neurons
Movement Disorders
Substantia Nigra
Haloperidol
Transgenic Mice
In Situ Hybridization
Pharmacology
Messenger RNA

Keywords

  • Adenosine
  • D2 dopamine receptor
  • Dystonia

ASJC Scopus subject areas

  • Neurology

Cite this

Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia. / Napolitano, Francesco; Pasqualetti, Massimo; Usiello, Alessandro; Santini, Emanuela; Pacini, Giulia; Sciamanna, Giuseppe; Errico, Francesco; Tassone, Annalisa; Di Dato, Valeria; Martella, Giuseppina; Cuomo, Dario; Fisone, Gilberto; Bernardi, Giorgio; Mandolesi, Georgia; Mercuri, Nicola B.; Standaert, David G.; Pisani, Antonio.

In: Neurobiology of Disease, Vol. 38, No. 3, 06.2010, p. 434-445.

Research output: Contribution to journalArticle

Napolitano, F, Pasqualetti, M, Usiello, A, Santini, E, Pacini, G, Sciamanna, G, Errico, F, Tassone, A, Di Dato, V, Martella, G, Cuomo, D, Fisone, G, Bernardi, G, Mandolesi, G, Mercuri, NB, Standaert, DG & Pisani, A 2010, 'Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia', Neurobiology of Disease, vol. 38, no. 3, pp. 434-445. https://doi.org/10.1016/j.nbd.2010.03.003
Napolitano, Francesco ; Pasqualetti, Massimo ; Usiello, Alessandro ; Santini, Emanuela ; Pacini, Giulia ; Sciamanna, Giuseppe ; Errico, Francesco ; Tassone, Annalisa ; Di Dato, Valeria ; Martella, Giuseppina ; Cuomo, Dario ; Fisone, Gilberto ; Bernardi, Giorgio ; Mandolesi, Georgia ; Mercuri, Nicola B. ; Standaert, David G. ; Pisani, Antonio. / Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia. In: Neurobiology of Disease. 2010 ; Vol. 38, No. 3. pp. 434-445.
@article{00ab0b70acb94b3ca5e74420cd06d6dd,
title = "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.",
keywords = "Adenosine, D2 dopamine receptor, Dystonia",
author = "Francesco Napolitano and Massimo Pasqualetti and Alessandro Usiello and Emanuela Santini and Giulia Pacini and Giuseppe Sciamanna and Francesco Errico and Annalisa Tassone and {Di Dato}, Valeria and Giuseppina Martella and Dario Cuomo and Gilberto Fisone and Giorgio Bernardi and Georgia Mandolesi and Mercuri, {Nicola B.} and Standaert, {David G.} and Antonio Pisani",
year = "2010",
month = "6",
doi = "10.1016/j.nbd.2010.03.003",
language = "English",
volume = "38",
pages = "434--445",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia

AU - Napolitano, Francesco

AU - Pasqualetti, Massimo

AU - Usiello, Alessandro

AU - Santini, Emanuela

AU - Pacini, Giulia

AU - Sciamanna, Giuseppe

AU - Errico, Francesco

AU - Tassone, Annalisa

AU - Di Dato, Valeria

AU - Martella, Giuseppina

AU - Cuomo, Dario

AU - Fisone, Gilberto

AU - Bernardi, Giorgio

AU - Mandolesi, Georgia

AU - Mercuri, Nicola B.

AU - Standaert, David G.

AU - Pisani, Antonio

PY - 2010/6

Y1 - 2010/6

N2 - 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.

AB - 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.

KW - Adenosine

KW - D2 dopamine receptor

KW - Dystonia

UR - http://www.scopus.com/inward/record.url?scp=77952542997&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952542997&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2010.03.003

DO - 10.1016/j.nbd.2010.03.003

M3 - Article

C2 - 20227500

AN - SCOPUS:77952542997

VL - 38

SP - 434

EP - 445

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

IS - 3

ER -