Neuronal scaffolding protein spinophilin is integral for cocaine-induced behavioral sensitization and ERK1/2 activation
Neuronal scaffolding protein spinophilin is integral for cocaine-induced behavioral sensitization and ERK1/2 activation
复制标题
DOI：
10.1186/s13041-019-0434-7
复制
发表时间：
2019-02-25
期刊：
影响因子：
3.6
通讯作者：
Ferguson, Stephen S. G.
中科院分区：
文献类型：
--
作者：
Areal, Lorena Bianchine;Hamilton, Alison;Ferguson, Stephen S. G.
嗜刺素是一种富含树突棘的支架蛋白，在调节树突棘密度和形态以及调节突触可塑性方面发挥重要作用。亲棘素改变突触强度的能力似乎涉及其关键突触蛋白的支架，包括重要的结构元件F-肌动蛋白、AMPA/NMDA调节蛋白磷酸酶1和神经调节G-蛋白偶联受体，包括多巴胺受体D2和代谢型谷氨酸受体5。此外，亲棘素在纹状体中高度表达，纹状体是一个基本上参与奖励处理和运动活动的脑区域，其接收多巴胺能和多巴胺能输入。因此，我们的目的是调查的作用，在可卡因的行为反应，评估野生型和spinophilin基因敲除小鼠，然后检查潜在的分子改变。虽然急性运动反应不受影响，但删除spinophilin阻断了可卡因行为敏化的发展和表达，同时保持正常的条件性位置偏爱。这种行为的改变，在spinophilin基因敲除小鼠伴随着减弱c-Fos和FosB表达可卡因管理和钝可卡因诱导的磷酸化ERK 1/2在纹状体，在其他相关的信号分子没有变化。因此，我们认为，亲棘素履行可卡因诱导的行为敏化，可能通过ERK 1/2磷酸化和诱导c-Fos和FosB在纹状体，一种机制，可能是可卡因成瘾的特定过程的基础上的重要作用。
Spinophilin is a scaffolding protein enriched in dendritic spines with integral roles in the regulation of spine density and morphology, and the modulation of synaptic plasticity. The ability of spinophilin to alter synaptic strength appears to involve its scaffolding of key synaptic proteins, including the important structural element F-actin, AMPA/NMDA modulator protein phosphatase 1, and neuromodulatory G-protein coupled receptors, including dopamine receptor D2 and metabotropic glutamate receptor 5. Additionally, spinophilin is highly expressed in the striatum, a brain region that is fundamentally involved in reward-processing and locomotor activity which receives both glutamatergic and dopaminergic inputs. Therefore, we aimed to investigate the role of spinophilin in behavioral responses to cocaine, evaluating wild-type and spinophilin knockout mice followed by the examination of underlying molecular alterations. Although acute locomotor response was not affected, deletion of spinophilin blocked the development and expression of behavioral sensitization to cocaine while maintaining normal conditioned place preference. This behavioral alteration in spinophilin knockout mice was accompanied by attenuated c-Fos and FosB expression following cocaine administration and blunted cocaine-induced phosphorylation of ERK1/2 in the striatum, with no change in other relevant signaling molecules. Therefore, we suggest spinophilin fulfills an essential role in cocaine-induced behavioral sensitization, likely via ERK1/2 phosphorylation and induction of c-Fos and FosB in the striatum, a mechanism that may underlie specific processes in cocaine addiction.