Kells A P, Henry R A, Connor B
Department of Pharmacology and Clinical Pharmacology, Neural Repair and Neurogenesis Laboratory, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Gene Ther. 2008 Jul;15(13):966-77. doi: 10.1038/gt.2008.23. Epub 2008 Mar 6.
Maintenance and plasticity of striatal neurons is dependent on brain-derived neurotrophic factor (BDNF), which is depleted in the Huntington's disease striatum due to reduced expression and disrupted corticostriatal transportation. In this study we demonstrate that overexpression of BDNF in the striatum attenuates motor impairment and reduces the extent of striatal damage following quinolinic acid lesioning. Transfer of the BDNF gene to striatal neurons using serotype 1/2 adeno-associated viral vectors enhanced BDNF protein levels in the striatum, but induced weight loss and seizure activity following long-term high-level expression. Lower concentration BDNF expression supported striatal neurons against excitotoxic insult, as demonstrated by enhanced krox-24 immunopositive neuron survival, reduction of striatal atrophy and maintenance of the patch/matrix organization. Additionally, BDNF expression attenuated motor impairment in the forelimb use cylinder test, sensorimotor neglect in the corridor food selection task and reversed apomorphine-induced rotational behaviour. Direct correlations were shown for the first time between BDNF-mediated attenuation of behavioural impairment and the integrity of the globus pallidus, seemingly independent from the severity of striatal lesioning. These results demonstrate that BDNF holds considerable therapeutic potential for alleviating both neuropathological and motor function deficits in the Huntington's disease brain, and the critical role of pallidal neurons in facilitating motor performance.
纹状体神经元的维持和可塑性依赖于脑源性神经营养因子（BDNF），由于其表达减少和皮质纹状体运输中断，该因子在亨廷顿病纹状体中含量降低。在本研究中，我们证明纹状体内BDNF的过表达可减轻运动障碍，并减少喹啉酸损伤后纹状体损伤的程度。使用1/2型腺相关病毒载体将BDNF基因转移至纹状体神经元可提高纹状体内BDNF蛋白水平，但长期高水平表达后会导致体重减轻和癫痫发作。较低浓度的BDNF表达可保护纹状体神经元免受兴奋性毒性损伤，这表现为krox-24免疫阳性神经元存活率提高、纹状体萎缩减轻以及纹片/基质组织结构得以维持。此外，BDNF表达减轻了前肢使用圆筒试验中的运动障碍、走廊食物选择任务中的感觉运动忽视，并逆转了阿扑吗啡诱导的旋转行为。首次表明BDNF介导的行为障碍减轻与苍白球的完整性之间存在直接关联，这似乎与纹状体损伤的严重程度无关。这些结果表明，BDNF在减轻亨廷顿病脑中的神经病理学和运动功能缺陷方面具有巨大的治疗潜力，以及苍白球神经元在促进运动表现中的关键作用。
