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 language | English |
|---|---|
| Pages (from-to) | 133-145 |
| Number of pages | 13 |
| Journal | Neurobiology of Disease |
| Volume | 34 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Apr 2009 |
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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 journal › Article
}
TY - JOUR
T1 - Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia
AU - Sciamanna, Giuseppe
AU - Bonsi, Paola
AU - Tassone, Annalisa
AU - Cuomo, Dario
AU - Tscherter, Anne
AU - Viscomi, Maria Teresa
AU - Martella, Giuseppina
AU - Sharma, Nutan
AU - Bernardi, Giorgio
AU - Standaert, David G.
AU - Pisani, Antonio
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
KW - D2 dopamine receptor
KW - Dystonia
KW - Electrophysiology
KW - Fast-spiking interneuron
KW - Medium Spiny neurons
UR - http://www.scopus.com/inward/record.url?scp=62149127782&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62149127782&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2009.01.001
DO - 10.1016/j.nbd.2009.01.001
M3 - Article
C2 - 19187797
AN - SCOPUS:62149127782
VL - 34
SP - 133
EP - 145
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 1
ER -