Ghilan Mohamed, Bostrom Crystal A, Hryciw Brett N, Simpson Jessica M, Christie Brian R, Gil-Mohapel Joana
Division of Medical Sciences, Island Medical Program, University of Victoria, Victoria, BC, Canada; Department of Biology, University of Victoria, Victoria, BC, Canada.
Division of Medical Sciences, Island Medical Program, University of Victoria, Victoria, BC, Canada.
Brain Res. 2014 Sep 18;1581:117-28. doi: 10.1016/j.brainres.2014.06.011. Epub 2014 Jun 17.
Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the protein huntingtin. The disease progresses over decades, but often patients develop cognitive impairments that precede the onset of the classical motor symptoms. Similar to the disease progression in humans, the yeast artificial chromosome (YAC) 128 HD mouse model also exhibits cognitive dysfunction that precedes the onset of the neuropathological and motor impairments characteristic of HD. Thus, the purpose of this study was to evaluate whether short- and long-term synaptic plasticity in the hippocampus, two related biological models of learning and memory processes, were altered in YAC128 mice in early stages of disease progression. We show that the YAC128 hippocampal dentate gyrus (DG) displays marked reductions in paired-pulse depression both at 3 and 6 months of age. In addition, significantly enhanced post-tetanic and short-term potentiation are apparent in YAC128 mice after high-frequency stimulation at this time. Early and late forms of long-term plasticity were not altered at this stage. Together these findings indicate that there may be elevated neurotransmitter release in response to synaptic stimulation in YAC128 mice during the initial phase of disease progression. These abnormalities in short-term plasticity detected at this stage in YAC128 HD transgenic mice indicate that aberrant information processing at the level of the synapses may contribute, at least in part, to the early onset of cognitive deficits that are characteristic of this devastating neurodegenerative disorder.
亨廷顿舞蹈症（HD）是一种进行性致命的神经退行性疾病，由编码亨廷顿蛋白的基因中的多聚谷氨酰胺扩展引起。该疾病会持续数十年，但患者通常在经典运动症状出现之前就会出现认知障碍。与人类疾病进展相似，酵母人工染色体（YAC）128 HD小鼠模型也表现出认知功能障碍，且早于HD特有的神经病理学和运动障碍出现。因此，本研究的目的是评估在疾病进展早期阶段，YAC128小鼠中学习和记忆过程的两个相关生物学模型——海马体中的短期和长期突触可塑性是否发生改变。我们发现，YAC128海马齿状回（DG）在3个月和6个月大时，配对脉冲抑制均显著降低。此外，此时对YAC128小鼠进行高频刺激后，强直后增强和短期增强明显增强。长期可塑性的早期和晚期形式在此阶段未发生改变。这些发现共同表明，在疾病进展的初始阶段，YAC128小鼠可能会因突触刺激而增加神经递质释放。在这个阶段，YAC128 HD转基因小鼠中检测到的短期可塑性异常表明，突触水平的异常信息处理可能至少部分导致了这种毁灭性神经退行性疾病特有的认知缺陷的早期出现。
