Sciamanna Giuseppe, Bonsi Paola, Tassone Annalisa, Cuomo Dario, Tscherter Anne, Viscomi Maria Teresa, Martella Giuseppina, Sharma Nutan, Bernardi Giorgio, Standaert David G, Pisani Antonio
Department of Neuroscience, University "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
Neurobiol Dis. 2009 Apr;34(1):133-45. doi: 10.1016/j.nbd.2009.01.001. Epub 2009 Jan 13.
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.
DYT1型肌张力障碍是由扭转蛋白A C末端的一个谷氨酸残基缺失引起的，其功能在很大程度上仍不清楚。GABA能信号的改变与肌张力障碍的发病机制有关。我们从DYT1型肌张力障碍小鼠模型的纹状体切片标本中记录了GABA和谷氨酸介导的突触电流。在表达人类突变扭转蛋白A（hMT）的小鼠的中等棘状神经元（MSN）中，我们观察到GABA能自发性抑制性突触后电流（sIPSC）和微小电流（mIPSC）的频率显著升高，但幅度未变，而谷氨酸依赖性自发性兴奋性突触电流（sEPSC）正常。在过表达正常人类扭转蛋白A（hWT）的小鼠中未发现改变。为了确定GABA能张力增加的可能来源，我们记录了对MSN施加前馈抑制的GABA能快速发放（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受体在突触前起作用以减少纹状体GABA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小鼠MSN中sIPSC的频率。同样，喹吡罗对hMT小鼠MSN和FS中间神经元诱发的IPSC的抑制作用也丧失了。我们的研究结果表明纹状体GABA能突触活动去抑制，这至少部分可归因于D2 DA受体功能障碍。
