Tonic mGluR5/CB1-dependent suppression of inhibition as a pathophysiological hallmark in the striatum of mice carrying a mutant form of huntingtin
Tonic mGluR5/CB1-dependent suppression of inhibition as a pathophysiological hallmark in the striatum of mice carrying a mutant form of huntingtin
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DOI：
10.1113/jphysiol.2012.241018
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发表时间：
2013-02-01
影响因子：
5.5
通讯作者：
Grantyn, Rosemarie
中科院分区：
文献类型：
--
作者：
Dvorzhak, Anton;Semtner, Marcus;Grantyn, Rosemarie
在神经退行性疾病中，受累的大脑提供了一个重要的研究对象，也提供了一个从病理生理学角度描述给定细胞相互作用的机会。中心点当人类疾病基于单基因缺陷并且有适当的动物模型可用于详细研究时，这种双重方法特别有利，例如Z_Q175_KI，一种表达鼠亨廷顿蛋白突变形式的新型敲入小鼠。中心点我们的结果挑战了目前关于亨廷顿病纹状体中GABA能传递增强的观点。结合高频刺激和成对脉冲测试的量子分析显示，突触GABA释放实际上是紧张性抑制，导致纹状体输出活动的去抑制。中心点潜在的机制涉及连接突触后代谢型谷氨酸5型受体与突触前大麻素1型受体和GABA释放的逆行内源性大麻素信号通路。结果帮助我们理解为什么细胞外谷氨酸水平的病理性升高会抑制突触抑制。摘要纹状体输出神经元（SONs）活性的改变与亨廷顿病（HD）的发病机制有关。在这种遗传性多聚谷氨酰胺疾病中，细胞内毒素的积累导致各种缺陷，包括突触功能障碍，但仍不清楚纹状体GABA释放的程度。使用了两种鼠HD模型，一种是最近创建的基因敲入小鼠（Z_Q175_KI），另一种是已建立的HD模型（R6/2）。在基底神经节中具有相对完好的GABA能连接的矢状切片中，我们描述了以下特征：（i）SON的兴奋性;（ii）它们的自发动作电位依赖性GABA能突触活动;（iii）外源性GABA抑制自发动作电位产生的能力;和（iv）GABA能单一诱发反应（eIPSC）响应于低和高频率的纹状体内最小刺激的性质。HD SONs表现出增强的神经兴奋性和更高水平的GABA能自发活动，而没有提供内源性或外源性GABA作用的稳态上调的证据。单一eIPSC振幅降低，释放概率明显不足，如较高的配对脉冲比、故障率和变异系数所示。在高频激活条件下，HD SON的GABA能连接倾向于异步释放和延迟IPSC产生，代价是同步释放。在野生型和HD SONs中，GABA均具有抑制作用。我们的研究结果支持的结论，增强自发性突触活动在HD纹状体反映去抑制。药理学测试确定了HD相关的紧张性抑制突触抑制作为谷氨酸和内源性大麻素依赖性过程。
Key points center dot In neurodegenerative diseases, the afflicted brain provides both an important object of study and an opportunity to characterize a given cellular interaction from a pathophysiological perspective. center dot This dual approach is particularly advantageous when human disease is based on a monogenetic defect and an appropriate animal model becomes available for detailed investigation, as in case of Z_Q175_KI, a new knock-in mouse expressing a mutant form of murine huntingtin. center dot Our results challenge the current viewpoint that GABAergic transmission is enhanced in the striatum in Huntington's disease. Quantal analysis in combination with high-frequency stimulation and paired-pulse tests revealed that synaptic GABA release is in fact tonically suppressed, resulting in disinhibition of striatal output activity. center dot The underlying mechanism involves a retrograde endocannabinoid signalling pathway linking postsynaptic metabotropic glutamate type 5 receptors with presynaptic cannabinoid type 1 receptors and GABA release. center dot The results help us to understand why pathological elevation of extracellular glutamate levels depresses synaptic inhibition. Abstract Changes in the activity of striatal output neurons (SONs) have been implicated in the pathogenesis of Huntington's disease (HD). In this inherited polyglutamine disorder, accumulation of intracellular toxins causes a variety of deficits, including synaptic dysfunction, but it is still unclear to what extent striatal GABA release is afflicted as well. Two murine HD models were used, a recently created knock-in mouse (Z_Q175_KI) and an established model of HD (R6/2). In sagittal slices with relatively well-preserved glutamatergic connections throughout the basal ganglia, we have characterized the following: (i) the excitability of SONs; (ii) their spontaneous action potential-dependent GABAergic synaptic activity; (iii) the capacity of exogenous GABA to inhibit spontaneous action potential generation; and (iv) the properties of GABAergic unitary evoked responses (eIPSCs) in response to intrastriatal minimal stimulation at low and high frequency. The HD SONs exhibited enhanced intrisic excitability and higher levels of GABAergic spontaneous activity without presenting evidence for homeostatic upregulation of endogenous or exogenous GABA actions. Unitary eIPSC amplitudes were reduced, with a clear deficit in the probability of release, as indicated by a higher paired-pulse ratio, failure rate and coefficient of variation. In conditions of high-frequency activation, GABAergic connections of HD SONs were prone to asynchronous release and delayed IPSC generation at the expense of synchronized release. Both in wild-type and in HD SONs, GABA was inhibitory. Our results support the conclusion that the enhanced spontaneous synaptic activity in the HD striatum reflects disinhibition. Pharmacological tests identified the HD-related tonic suppression of synaptic inhibition as a glutamate- and endocannabinoid-dependent process.