Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, M5S 3G5, Canada.
Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, M5S 3G5, Canada.
Neuroscience. 2019 Apr 15;404:130-140. doi: 10.1016/j.neuroscience.2019.02.007. Epub 2019 Feb 22.
Huntington's disease (HD) is a genetic neurodegenerative disorder of the central nervous system characterized by choreatic movements, behavioral and psychiatric disturbances and cognitive impairments. Deficits in learning and memory are often the first signs of disease onset in both HD patients and mouse models of HD and are in part regulated by the hippocampus. In the R6/2 mouse model of HD, GABAergic transmission can be excitatory in the hippocampus and restoring inhibition can rescue the associated memory deficits. In the present study we determine that hippocampal GABAergic neurotransmission in the R6/2 mouse is disrupted as early as 4 weeks of age and is accompanied by alterations in the expression of key inhibitory proteins. Specifically, spontaneous inhibitory postsynaptic currents were initially increased in frequency at 4 postnatal weeks and subsequently decreased after the mice displayed the typical R6/2 behavioral phenotype at 10 weeks of age. Symptomatic mice also exhibited a change in the probability of GABA release and changes in the basic membrane properties including neuronal excitability and input resistance. These electrophysiological changes in presymptomatic and symptomatic R6/2 mice were further accompanied by alterations in the protein expression level of pre- and postsynaptic inhibitory markers. Taken together, the present findings demonstrate profound alterations in the inhibitory neurotransmission in the hippocampus across the lifespan of the disease, including prior to neuronal degeneration, which suggests that the inhibitory hippocampal synapses may prove useful as a target for future therapeutic design.
亨廷顿病（HD）是一种中枢神经系统的遗传性神经退行性疾病，其特征为舞蹈运动、行为和精神障碍以及认知障碍。学习和记忆缺陷通常是 HD 患者和 HD 小鼠模型疾病发作的最初迹象，部分受海马体调节。在 R6/2 HD 小鼠模型中，海马体中的 GABA 能传递可以是兴奋性的，恢复抑制作用可以挽救相关的记忆缺陷。在本研究中，我们确定 R6/2 小鼠的海马 GABA 能神经传递早在 4 周龄时就被破坏，并伴随着关键抑制蛋白表达的改变。具体来说，在 4 周龄时，自发性抑制性突触后电流的频率最初增加，随后在 10 周龄时小鼠表现出典型的 R6/2 行为表型后减少。有症状的小鼠还表现出 GABA 释放概率的变化以及基本膜特性的变化，包括神经元兴奋性和输入电阻。这些 R6/2 小鼠在预症状和症状期的电生理变化进一步伴随着突触前和突触后抑制性标志物的蛋白表达水平的改变。总之，这些发现表明，疾病整个生命周期的海马体抑制性神经传递发生了深刻的改变，包括在神经元变性之前，这表明抑制性海马突触可能是未来治疗设计的一个有用靶点。
