MPTP-induced deficits in striatal synaptic plasticity are prevented by glial cell line-derived neurotrophic factor expressed via an adeno-associated viral vector
MPTP-induced deficits in striatal synaptic plasticity are prevented by glial cell line-derived neurotrophic factor expressed via an adeno-associated viral vector
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DOI：
10.1096/fj.07-8797com
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发表时间：
2008-01-01
期刊：
影响因子：
4.8
通讯作者：
Lupica, Carl R.
中科院分区：
文献类型：
--
作者：
Chen, Yuan-Hao;Harvey, Brandon K.;Lupica, Carl R.
本研究确定了纹状体多巴胺去神经支配对突触可塑性的影响，并使用表达胶质细胞源性神经营养因子（GDNF）的腺相关病毒载体（AAV）进行基因治疗以预防这些变化。用神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）注射C57 BL 6/J小鼠，在体外测定长时程抑制（LTD）或增强（LTP）。快速扫描循环伏安法测量从这些纹状体切片中功能相关的池中电释放的多巴胺。MPTP后，纹状体脑片多巴胺的释放和摄取明显减少，LTP和LTD被阻断。可塑性的丧失直接来自多巴胺的丧失，因为多巴胺的应用挽救了突触的可塑性。纹状体GDNF表达通过AAV，MPTP之前，显着防止多巴胺的损失，并防止皮质纹状体LTP的封锁。这些数据表明，多巴胺在支持多种形式的纹状体可塑性方面发挥作用，并且通过腺相关病毒表达GDNF可以防止MPTP引起的多巴胺和纹状体可塑性丧失。我们认为多巴胺去神经后纹状体可塑性的损伤在帕金森病的病理学中起作用，并且神经营养因子的AAV表达代表了保护或减缓这些神经生物学缺陷的可行方法。
This study determined the consequences of dopamine denervation of the striatum on synaptic plasticity and prevention of these changes with gene therapy using an adeno-associated viral vector (AAV) expressing glial cell line-derived neurotrophic factor (GDNF). C57BL6/J mice were injected with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); long-term depression (LTD) or potentiation (LTP) were measured in vitro. Fast-scan cyclic voltammetry measured electrically released dopamine from a functionally relevant pool in these same striatal slices. After MPTP, dopamine release and uptake were greatly diminished, and LTP and LTD were blocked in the striatal slices. The loss of plasticity resulted directly from the loss of dopamine since its application rescued synaptic plasticity. Striatal GDNF expression via AAV, before MPTP, significantly protected against the loss of dopamine and prevented the blockade of corticostriatal LTP. These data demonstrate that dopamine plays a role in supporting several forms of striatal plasticity and that GDNF expression via AAV prevents the loss of dopamine and striatal plasticity caused by MPTP. We propose that impairment of striatal plasticity after dopamine denervation plays a role in the symptomology of Parkinson's disease and that AAV expression of neurotrophic factors represents a tenable approach to protecting against or slowing these neurobiological deficits.