title: Developmental profile of the aberrant dopamine D2 receptor response in striatal cholinergic interneurons in DYT1 dystonia.
abstract: BACKGROUND
  DYT1 dystonia, a severe form of genetically determined human dystonia, exhibits reduced penetrance among carriers and begins usually during adolescence. The reasons for such age dependence and variability remain unclear.
  
  
  RESULTS
  We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneurons at different ages in mice overexpressing human mutant torsinA (hMT). An abnormal excitatory response to the D2R agonist quinpirole was recorded at postnatal day 14, consisting of a membrane depolarization coupled to an increase in spiking frequency, and persisted unchanged at 3 and 9 months in hMT mice, compared to mice expressing wild-type human torsinA and non-transgenic mice. This response was blocked by the D2R antagonist sulpiride and depended upon G-proteins, as it was prevented by intrapipette GDP-β-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calcium abolished the paradoxical response to quinpirole. Finally, no gross morphological changes were observed during development.
  
  
  CONCLUSIONS
  These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystonia and persists along development, representing a susceptibility factor for symptom generation.
authors.affiliation: Department of Neuroscience, University Tor Vergata, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciamanna
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tassone
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Martella
authors.forename: Georgia
authors.initials: G
authors.lastname: Mandolesi
authors.forename: Francesca
authors.initials: F
authors.lastname: Puglisi
authors.forename: Dario
authors.initials: D
authors.lastname: Cuomo
authors.forename: Grazia
authors.initials: G
authors.lastname: Madeo
authors.forename: Giulia
authors.initials: G
authors.lastname: Ponterio
authors.forename: David George
authors.initials: DG
authors.lastname: Standaert
authors.forename: Paola
authors.initials: P
authors.lastname: Bonsi
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004421:Dystonia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D055724:Electrophysiological Phenomena; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017072:Neostriatum / Q000254:growth & development* / Q000473:pathology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018832:Molecular Chaperones; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; C108175:TOR1A protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000109:Acetylcholine; D002118:Calcium