Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family.
Functional alterations to the nigrostriatal system in mice lacking all three members of the synuclein family.
复制标题
缺乏突触核蛋白家族的所有三个成员的小鼠中骨纹状体系统的功能改变。
DOI：
10.1523/jneurosci.6194-10.2011
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发表时间：
2011-05-18
期刊：
影响因子：
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通讯作者：
Buchman VL
中科院分区：
文献类型：
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作者：
Anwar S;Peters O;Millership S;Ninkina N;Doig N;Connor-Robson N;Threlfell S;Kooner G;Deacon RM;Bannerman DM;Bolam JP;Chandra SS;Cragg SJ;Wade-Martins R;Buchman VL
突触核蛋白（α、β和γ）是高度同源的蛋白质，被认为在调节神经传递中起作用，并且在突触前末梢中大量发现。为了克服突触核蛋白蛋白之间的功能重叠，并了解它们在中纹状体多巴胺能神经元突触前信号传导中的作用，我们制作了缺乏突触核蛋白家族所有三个成员的小鼠。使用行为、生物化学、组织学和电化学技术的组合，在成年（4-14月龄）动物中评估了对中纹状体系统的影响。成年triple synuclein null（TKO）小鼠没有表现出明显的表型，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，并通过快速扫描循环伏安法检测到纹状体中诱发的多巴胺释放增加。多巴胺释放升高是特定的背侧而不是腹侧纹状体，并伴随着多巴胺组织含量的减少。我们证实了一个正常的突触超微结构和正常丰度的SNARE蛋白复合物在背侧纹状体。用影响多巴胺代谢的药物治疗TKO动物显示正常的合成速率，增强的周转率和减少的突触前纹状体多巴胺储存。我们的数据独特地揭示了突触核蛋白在调节中脑多巴胺神经元的特定群体的神经递质释放的重要性，通过不同于其他神经元中报道的机制。突触核蛋白的完全丧失导致突触前末梢处理多巴胺的变化，特别是在帕金森病（PD）中优先脆弱的那些区域，这一发现可能最终会影响疾病过程的选择性。
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 signalling 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 (4-14 month old) animals using a combination of behavioural, 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 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 which 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 (PD) may ultimately inform on the selectivity of the disease process.