Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom.
J Neurosci. 2011 May 18;31(20):7264-74. doi: 10.1523/JNEUROSCI.6194-10.2011.
The synucleins (α, β, and γ) are highly homologous proteins thought to play a role in regulating neurotransmission and are found abundantly in presynaptic terminals. To overcome functional overlap between synuclein proteins and to understand their role in presynaptic signaling from mesostriatal dopaminergic neurons, we produced mice lacking all three members of the synuclein family. The effect on the mesostriatal system was assessed in adult (4- to 14-month-old) animals using a combination of behavioral, biochemical, histological, and electrochemical techniques. Adult triple-synuclein-null (TKO) mice displayed no overt phenotype and no change in the number of midbrain dopaminergic neurons. TKO mice were hyperactive in novel environments and exhibited elevated evoked release of dopamine in the striatum detected with fast-scan cyclic voltammetry. Elevated dopamine release was specific to the dorsal not ventral striatum and was accompanied by a decrease of dopamine tissue content. We confirmed a normal synaptic ultrastructure and a normal abundance of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein complexes in the dorsal striatum. Treatment of TKO animals with drugs affecting dopamine metabolism revealed normal rate of synthesis, enhanced turnover, and reduced presynaptic striatal dopamine stores. Our data uniquely reveal the importance of the synuclein proteins in regulating neurotransmitter release from specific populations of midbrain dopamine neurons through mechanisms that differ from those reported in other neurons. The finding that the complete loss of synucleins leads to changes in dopamine handling by presynaptic terminals specifically in those regions preferentially vulnerable in Parkinson's disease may ultimately inform on the selectivity of the disease process.
突触核蛋白(α、β 和 γ)是高度同源的蛋白质,被认为在调节神经递质方面发挥作用,并在突触前末梢中大量存在。为了克服突触核蛋白之间的功能重叠,并了解它们在中脑多巴胺能神经元突触前信号传递中的作用,我们生产了缺乏突触核蛋白家族所有三个成员的小鼠。在成年(4 至 14 个月大)动物中,使用行为学、生物化学、组织学和电化学技术的组合来评估对中脑纹状体系统的影响。成年三突触核蛋白敲除(TKO)小鼠没有明显的表型,中脑多巴胺能神经元的数量也没有变化。TKO 小鼠在新环境中表现出过度活跃,并在快速扫描循环伏安法检测到的纹状体中表现出多巴胺释放增加。多巴胺释放升高是特异性的,仅限于背侧纹状体而不是腹侧纹状体,并且伴随着多巴胺组织含量的降低。我们在背侧纹状体中证实了正常的突触超微结构和 SNARE(可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体)蛋白复合物的正常丰度。用影响多巴胺代谢的药物处理 TKO 动物显示出正常的合成率、增强的周转率和减少的纹状体内多巴胺储存。我们的数据独特地揭示了突触核蛋白在通过与其他神经元报道的机制不同的机制调节特定中脑多巴胺神经元群体的神经递质释放中的重要性。完全缺失突触核蛋白会导致多巴胺处理发生变化的发现,特别是在帕金森病中优先易损的那些区域的突触前末梢中,可能最终会为疾病过程的选择性提供信息。