Department of Cellular and Molecular Medicine and University of Ottawa Brain and Mind Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.
Graduate Program in Neuroscience, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
Mol Brain. 2019 Feb 25;12(1):15. doi: 10.1186/s13041-019-0434-7.
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.
螺旋蛋白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着重要作用。螺旋蛋白改变突触强度的能力似乎涉及到它对关键突触蛋白的支架作用，包括重要的结构元件 F-肌动蛋白、AMPA/NMDA 调节剂蛋白磷酸酶 1 以及神经调节 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，螺旋蛋白在纹状体中高度表达，纹状体是一个与奖赏处理和运动活动密切相关的脑区，它同时接收谷氨酸能和多巴胺能的输入。因此，我们旨在研究螺旋蛋白在可卡因行为反应中的作用，评估野生型和螺旋蛋白敲除小鼠，然后检查潜在的分子改变。尽管急性运动反应不受影响，但螺旋蛋白缺失阻止了可卡因引起的行为敏化的发展和表达，同时保持了正常的条件性位置偏好。在螺旋蛋白敲除小鼠中，这种行为改变伴随着可卡因给药后 c-Fos 和 ∆FosB 表达的减弱，以及纹状体中 ERK1/2 磷酸化的减弱，而其他相关信号分子没有变化。因此，我们认为螺旋蛋白在可卡因引起的行为敏化中发挥着重要作用，可能通过 ERK1/2 磷酸化和诱导纹状体中的 c-Fos 和 ∆FosB，这一机制可能是可卡因成瘾特定过程的基础。
