Multiple Sources of Striatal Inhibition Are Differentially Affected in Huntington's Disease Mouse Models
Multiple Sources of Striatal Inhibition Are Differentially Affected in Huntington's Disease Mouse Models
复制标题
DOI：
10.1523/jneurosci.2137-12.2013
复制
发表时间：
2013-04-24
影响因子：
5.3
通讯作者：
Levine, Michael S.
中科院分区：
文献类型：
--
作者：
Cepeda, Carlos;Galvan, Laurie;Levine, Michael S.
在亨廷顿氏病（HD）小鼠模型中，在中型棘神经元（MSN）的亚群中，自发抑制性突触活动得到了增强，这可能会抑制纹状体输出。我们使用电生理学和光遗传学方法研究了抑制的潜在来源，以评估两个HD的转基因小鼠模型中的反馈和进料抑制。单个全细胞贴片钳记录表明，增加的GABA突触活动主要影响间接途径MSN。 MSN之间的双贴剂记录表明，HD小鼠中MSN之间的连通性降低。但是，尽管连通性在对照组中严格是单向的，但在HD小鼠中发生双向连通性。还确定了MSN中GABA活性增加的其他来源。来自快速峰值（FS）Interneuron-MSN对的双贴片记录在MSN中显示出更大但可变的振幅响应。一致，与对照小鼠相比，FS表达白蛋白表达的选择性光遗传学刺激在HD中诱导的振幅MSN响应明显更大。虽然通过激活单个持久性低阈值尖峰（PLT）中间神经元在记录的对中，MSN的响应没有差异，但这些神经元在这两个HD模型中都发出了更多的动作电位，从而为MSNS自发GABA Synaptic Attivation增加了另一种来源。对表达生长抑素的选择性光遗传学刺激，PLTS中间神经元没有发现HD小鼠中MSN的反应有任何显着差异。这些发现提供了有力的证据表明，在较小程度上，对HD中MSN的反馈抑制可能是增加间接途径MSN的GABA突触活动的来源。
In Huntington's disease (HD) mouse models, spontaneous inhibitory synaptic activity is enhanced in a subpopulation of medium-sized spiny neurons (MSNs), which could dampen striatal output. We examined the potential source(s) of increased inhibition using electrophysiological and optogenetic methods to assess feedback and feedforward inhibition in two transgenic mouse models of HD. Single whole-cell patch-clamp recordings demonstrated that increased GABA synaptic activity impinges principally on indirect pathway MSNs. Dual patch recordings between MSNs demonstrated reduced connectivity between MSNs in HD mice. However, while connectivity was strictly unidirectional in controls, in HD mice bidirectional connectivity occurred. Other sources of increased GABA activity in MSNs also were identified. Dual patch recordings from fast spiking (FS) interneuron-MSN pairs demonstrated greater but variable amplitude responses in MSNs. In agreement, selective optogenetic stimulation of parvalbumin-expressing, FS interneurons induced significantly larger amplitude MSN responses in HD compared with control mice. While there were no differences in responses of MSNs evoked by activating single persistent low-threshold spiking (PLTS) interneurons in recorded pairs, these interneurons fired more action potentials in both HD models, providing another source for increased frequency of spontaneous GABA synaptic activity in MSNs. Selective optogenetic stimulation of somatostatin-expressing, PLTS interneurons did not reveal any significant differences in responses of MSNs in HD mice. These findings provide strong evidence that both feedforward and to a lesser extent feedback inhibition to MSNs in HD can potentially be sources for the increased GABA synaptic activity of indirect pathway MSNs.