Distinct roles for spinophilin and neurabin in dopamine-mediated plasticity
Distinct roles for spinophilin and neurabin in dopamine-mediated plasticity
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DOI：
10.1016/j.neuroscience.2006.02.067
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Greengard, P
中科院分区：
文献类型：
--
作者：
Allen, PB;Zachariou, V;Greengard, P
蛋白磷酸酶1在兴奋性突触活动的调控中起主要作用，并受多巴胺的神经调节作用的控制。参与调节蛋白磷酸酶1活性的机制包括与结构相关的细胞骨架元件嗜脊髓蛋白和神经蛋白的相互作用，突触支架蛋白在树突棘中高度富集。用敲除小鼠测试了多巴胺相关神经调节对这些蛋白的需求。多巴胺d1介导的α -氨基-3-羟基-5-甲基-4-异恶唑丙酸受体活性的调节在神经素敲除小鼠的纹状体和前额叶皮质神经元中都缺乏；在嗜脊髓蛋白敲除小鼠中，这种缺陷仅在纹状体神经元中表现出来。在皮质纹状体突触，神经素敲除小鼠的长期增强是缺乏的，而嗜脊髓素敲除小鼠的则没有，并被D1受体激动剂拯救。相比之下，嗜脊髓蛋白敲除小鼠缺乏长期抑郁，而神经素敲除小鼠则没有，并通过D2受体激活得以恢复。神经素基因敲除小鼠自发性兴奋性突触后电流频率增加，而嗜脊髓素基因敲除小鼠则没有，这种作用通过D2受体激动剂的应用而正常化。两种基因敲除菌株在D1受体刺激下表现出GluR1 Ser（815）磷酸化的增强，并且在可卡因刺激下表现出增强的运动激活。这些效应可能与可卡因奖励分离，可卡因奖励仅在嗜脊髓蛋白敲除小鼠中增强，并伴随着立即早期基因诱导的增加。这些数据证实了多巴胺介导的反应需要突触支架，并进一步表明嗜脊髓素和神经素在多巴胺能信号转导和精神兴奋反应中发挥着不同的作用。(c) 2006年由Elsevier Ltd代表IBRO出版。
Protein phosphatase 1 plays a major role in the governance of excitatory synaptic activity, and is subject to control via the neuromodulatory actions of dopamine. Mechanisms involved in regulating protein phosphatase 1 activity include interactions with the structurally related cytoskeletal elements spinophilin and neurabin, synaptic scaffolding proteins that are highly enriched in dendritic spines. The requirement for these proteins in dopamine-related neuromodulation was tested using knockout mice. Dopamine D1-mediated regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor activity was deficient in both striatal and prefrontal cortical neurons from neurabin knockout mice; in spinophilin knockout mice this deficit was manifest only in striatal neurons. At corticostriatal synapses long-term potentiation was deficient in neurabin knockout mice, but not in spinophilin knockout mice, and was rescued by a D1 receptor agonist. In contrast, long-term depression was deficient in spinophilin knockout mice but not in neurabin knockout mice, and was rescued by D2 receptor activation. Spontaneous excitatory post-synaptic current frequency was increased in neurabin knockout mice, but not in spinophilin knockout mice, and this effect was normalized by D2 receptor agonist application. Both knockout strains displayed increased induction of GluR1 Ser(815) phosphorylation in response to D1 receptor stimulation in slices, and also displayed enhanced locomotor activation in response to cocaine administration. These effects could be dissociated from cocaine reward, which was enhanced only in spinophilin knockout mice, and was accompanied by increased immediate early gene induction. These data establish a requirement for synaptic scaffolding in dopamine-mediated responses, and further indicate that spinophilin and neurabin play distinct roles in dopaminergic signal transduction and psychostimulant response. (c) 2006 Published by Elsevier Ltd on behalf of IBRO.