Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia.
Impaired striatal D2 receptor function leads to enhanced GABA transmission in a mouse model of DYT1 dystonia.
复制标题
DOI：
10.1016/j.nbd.2009.01.001
复制
发表时间：
2009-04
影响因子：
6.1
通讯作者：
Pisani A
中科院分区：
文献类型：
--
作者：
Sciamanna G;Bonsi P;Tassone A;Cuomo D;Tscherter A;Viscomi MT;Martella G;Sharma N;Bernardi G;Standaert DG;Pisani A
DYT1 肌张力障碍是由蛋白质 torsinA C 端谷氨酸残基缺失引起的，其功能目前仍不清楚。 GABA 信号的改变与肌张力障碍的发病机制有关。我们从 DYT1 肌张力障碍小鼠模型获得的纹状体切片中记录了 GABA 和谷氨酸介导的突触电流。在表达人突变 torsinA (hMT) 的小鼠的中型多棘神经元 (MSN) 中，我们观察到 GABA 能自发抑制性突触后电流 (sIPSC) 和微型电流 (mIPSC) 的频率显着升高，但幅度不明显，而谷氨酸依赖性自发兴奋性突触电流 (sEPSC) 则正常。在过度表达正常人 torsinA (hWT) 的小鼠中未发现任何改变。为了确定 GABA 能音调增加的可能来源，我们记录了对 MSN 施加前馈抑制的 GABA 能快速尖峰 (FS) 中间神经元。然而，从 hMT FS 中间神经元记录的 sEPSC 和 sIPSC 与 hWT 和非转基因 (NT) 小鼠相当。在生理条件下，多巴胺 (DA) D2 受体在突触前发挥作用，减少纹状体 GABA 的释放。值得注意的是，与 hWT 和 NT 小鼠相比，应用 D2 样受体激动剂喹吡罗未能降低 hMT 的 MSN 中 sIPSC 的频率。同样，喹吡罗对 hMT 小鼠 MSN 和 FS 中间神经元中诱发的 IPSC 的抑制作用消失。我们的研究结果表明纹状体 GABA 突触活性的去抑制，这至少部分归因于 D2 DA 受体功能障碍。
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.
登录
查看更多内容
DOI：
10.1073/pnas.0701185104
发表时间：
2007-04-24
影响因子：
11.1
作者：
Hewett, Jeffrey W.;Tannous, Bakhos;Breakefield, Xandra O.
通讯作者：
Breakefield, Xandra O.
影响因子：
7.6
作者：
Centonze, D;Picconi, B;Calabresi, P
通讯作者：
Calabresi, P
影响因子：
5.3
作者：
Narushima, Madoka;Uchigashima, Motokazu;Kano, Masanobu
通讯作者：
Kano, Masanobu
影响因子：
2.5
作者：
LEMOINE, C;TISON, F;BLOCH, B
通讯作者：
BLOCH, B
影响因子：
6.1
作者：
Grundmann, K.;Reischmann, B.;Riess, O.
通讯作者：
Riess, O.