Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo
Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo
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DOI：
10.1073/pnas.1402134111
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发表时间：
2014-07-08
影响因子：
11.1
通讯作者：
Miller, Gary W.
中科院分区：
文献类型：
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作者：
Lohr, Kelly M.;Bernstein, Alison I.;Miller, Gary W.
神经递质囊泡动力学（运输，容量，释放）的破坏已牵连在各种神经退行性和神经精神疾病。在这里，我们报告了一种新的小鼠模型，通过细菌人工染色体（BAC）介导的过表达的囊泡单胺转运蛋白2（VMAT2; Slc18a2）增强囊泡功能。在小鼠纹状体中，囊泡运输的两倍增加增强了多巴胺的囊泡容量（56%）、多巴胺囊泡体积（33%）和基底组织多巴胺水平（21%）。囊泡容量升高导致刺激多巴胺释放（84%）和细胞外多巴胺水平（44%）增加。VMAT2过表达小鼠在焦虑和抑郁样行为方面表现出改善的结果，并增加了基础运动活动（41%）。最后，这些小鼠表现出对多巴胺能毒物1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的神经毒性损伤的显著保护，如通过减少多巴胺末端损伤和黑质丘脑部细胞损失所测量的。在VMAT2过表达小鼠中，多巴胺的释放增加和MPTP毒性的神经保护作用表明，旨在增强囊泡容量的干预措施可能对帕金森病具有治疗益处。
Disruption of neurotransmitter vesicle dynamics (transport, capacity, release) has been implicated in a variety of neurodegenerative and neuropsychiatric conditions. Here, we report a novel mouse model of enhanced vesicular function via bacterial artificial chromosome (BAC)-mediated overexpression of the vesicular monoamine transporter 2 (VMAT2; Slc18a2). A twofold increase in vesicular transport enhances the vesicular capacity for dopamine (56%), dopamine vesicle volume (33%), and basal tissue dopamine levels (21%) in the mouse striatum. The elevated vesicular capacity leads to an increase in stimulated dopamine release (84%) and extracellular dopamine levels (44%). VMAT2-overexpressing mice show improved outcomes on anxiety and depressive-like behaviors and increased basal locomotor activity (41%). Finally, these mice exhibit significant protection from neurotoxic insult by the dopaminergic toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), as measured by reduced dopamine terminal damage and substantia nigra pars compacta cell loss. The increased release of dopamine and neuroprotection from MPTP toxicity in the VMAT2-overexpressing mice suggest that interventions aimed at enhancing vesicular capacity may be of therapeutic benefit in Parkinson disease.