Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia

Giuseppe Sciamanna, Paola Bonsi, Annalisa Tassone, Dario Cuomo, Anne Tscherter, Maria Teresa Viscomi, Giuseppina Martella, Nutan Sharma, Giorgio Bernardi, David G. Standaert, Antonio Pisani

Research output: Contribution to journalArticle

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Abstract

DYT1 dystonia is caused by a deletion in a glutamic acid residue in the C-terminus of the protein torsinA, whose function is still largely unknown. Alterations in GABAergic signaling have been involved in the pathogenesis of dystonia. We recorded GABA- and glutamate-mediated synaptic currents from a striatal slice preparation obtained from a mouse model of DYT1 dystonia. In medium spiny neurons (MSNs) from mice expressing human mutant torsinA (hMT), we observed a significantly higher frequency, but not amplitude, of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature currents (mIPSCs), whereas glutamate-dependent spontaneous excitatory synaptic currents (sEPSCs) were normal. No alterations were found in mice overexpressing normal human torsinA (hWT). To identify the possible sources of the increased GABAergic tone, we recorded GABAergic Fast-Spiking (FS) interneurons that exert a feed-forward inhibition on MSNs. However, both sEPSC and sIPSC recorded from hMT FS interneurons were comparable to hWT and non-transgenic (NT) mice. In physiological conditions, dopamine (DA) D2 receptor act presynaptically to reduce striatal GABA release. Of note, application of the D2-like receptor agonist quinpirole failed to reduce the frequency of sIPSCs in MSNs from hMT as compared to hWT and NT mice. Likewise, the inhibitory effect of quinpirole was lost on evoked IPSCs both in MSNs and FS interneurons from hMT mice. Our findings demonstrate a disinhibition of striatal GABAergic synaptic activity, that can be at least partially attributed to a D2 DA receptor dysfunction.

Original languageEnglish
Pages (from-to)133-145
Number of pages13
JournalNeurobiology of Disease
Volume34
Issue number1
DOIs
Publication statusPublished - Apr 2009

Fingerprint

Corpus Striatum
Dystonia
gamma-Aminobutyric Acid
Inhibitory Postsynaptic Potentials
Interneurons
Quinpirole
Neurons
Glutamic Acid
Dopamine D2 Receptors
Protein C

Keywords

  • D2 dopamine receptor
  • Dystonia
  • Electrophysiology
  • Fast-spiking interneuron
  • Medium Spiny neurons

ASJC Scopus subject areas

  • Neurology

Cite this

Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia. / Sciamanna, Giuseppe; Bonsi, Paola; Tassone, Annalisa; Cuomo, Dario; Tscherter, Anne; Viscomi, Maria Teresa; Martella, Giuseppina; Sharma, Nutan; Bernardi, Giorgio; Standaert, David G.; Pisani, Antonio.

In: Neurobiology of Disease, Vol. 34, No. 1, 04.2009, p. 133-145.

Research output: Contribution to journalArticle

Sciamanna, G, Bonsi, P, Tassone, A, Cuomo, D, Tscherter, A, Viscomi, MT, Martella, G, Sharma, N, Bernardi, G, Standaert, DG & Pisani, A 2009, 'Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia', Neurobiology of Disease, vol. 34, no. 1, pp. 133-145. https://doi.org/10.1016/j.nbd.2009.01.001
Sciamanna, Giuseppe ; Bonsi, Paola ; Tassone, Annalisa ; Cuomo, Dario ; Tscherter, Anne ; Viscomi, Maria Teresa ; Martella, Giuseppina ; Sharma, Nutan ; Bernardi, Giorgio ; Standaert, David G. ; Pisani, Antonio. / Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia. In: Neurobiology of Disease. 2009 ; Vol. 34, No. 1. pp. 133-145.
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