Department of Psychiatry and Brain Research Centre, University of British Columbia, Vancouver, Canada.
Trends Neurosci. 2010 Nov;33(11):513-23. doi: 10.1016/j.tins.2010.08.002. Epub 2010 Sep 17.
Investigations of synaptic transmission and plasticity in mouse models of Huntington's disease (HD) demonstrate neuronal dysfunction long before the onset of classical disease indicators. Similarly, recent human studies reveal synaptic dysfunction decades before predicted clinical diagnosis in HD gene carriers. These studies guide premanifest tracking of disease and the development of treatment assessment tools. New discoveries of mechanisms underlying early neuronal dysfunction, including elevated pathogenic extrasynaptic NMDA receptor signaling, reduced synaptic connectivity and loss of brain-derived neurotrophic factor (BDNF) support have led to pharmacological interventions that can reverse or delay phenotype onset and disease progression in HD mice. Further understanding the primary effects of gene mutations associated with late-onset neurodegeneration should translate to novel treatments for HD families and guide therapeutic strategies for other neurodegenerative diseases.
在亨廷顿病（HD）的小鼠模型中进行的突触传递和可塑性研究表明，在出现经典疾病标志物之前，神经元功能就已经出现障碍。同样，最近的人类研究也表明，在 HD 基因携带者出现可预测的临床诊断前数十年，就已经出现了突触功能障碍。这些研究为疾病的临床前跟踪和治疗评估工具的开发提供了指导。对早期神经元功能障碍的潜在机制的新发现，包括升高的致病性细胞外 NMDA 受体信号、突触连接减少和脑源性神经营养因子（BDNF）的丧失，为药物干预提供了支持，这些干预措施可以逆转或延迟 HD 小鼠的表型发作和疾病进展。进一步了解与迟发性神经退行性变相关的基因突变的主要影响，应该可以为 HD 患者提供新的治疗方法，并为其他神经退行性疾病的治疗策略提供指导。
