Down-regulation of dorsal striatal alpha CaMKII causes striatum-related cognitive and synaptic disorders
Down-regulation of dorsal striatal alpha CaMKII causes striatum-related cognitive and synaptic disorders
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背侧纹状体 α CaMKII 下调导致纹状体相关认知和突触障碍
DOI：
10.1016/j.expneurol.2017.09.004
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发表时间：
2017
影响因子：
5.3
通讯作者：
Cao Xiaohua
中科院分区：
文献类型：
--
作者：
Wang Qi;Yin Pengcheng;Yu Bin;Zhao Zheng;Richter-Levin Gal;Yu Lu;Cao Xiaohua
α钙/钙调素依赖性蛋白激酶II（αCaMKII）是一种丝氨酸/苏氨酸蛋白激酶，在背侧纹状体大量表达，与皮质纹状体突触可塑性密切相关。尽管如此，目前尚不清楚αCaMKII是否以及如何在纹状体相关神经疾病中发挥作用。为了解决上述问题，本研究采用慢病毒介导的短发夹RNA（shRNA）沉默小鼠背侧纹状体α CaMK Ⅱ基因的表达。由于背侧纹状体αCaMKII表达下调，我们观察到在加速旋转棒中的运动技能学习和在水十字迷宫中的反应学习缺陷。此外，在αCaMKII-shRNA小鼠中还检测到与背侧纹状体相关认知缺陷相关的皮质纹状体基底传递和长时程增强（LTP）受损。与上述结果一致，αCaMKII-shRNA小鼠表现出α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）GluA 1-Ser 831和GluA 1-Ser 845磷酸化水平的显著下降，以及N-甲基-d-天冬氨酸受体（NMDAR）亚基NR 1、NR 2A和NR 2B表达水平的下降。总而言之，αCaMKII下调通过抑制皮质纹状体突触可塑性（由AMPAR和NMDAR功能障碍引起）而导致背侧纹相关的认知障碍。我们的研究结果首次证明了α CaMK II在纹状体相关神经疾病中的重要作用，并为皮质纹状体LTP是背侧纹状体相关认知的基础这一命题提供了进一步的证据。
Alpha calcium/calmodulin dependent protein kinase II (αCaMKII) is a serine/threonine protein kinase which is expressed abundantly in dorsal striatum and is highly involved in the corticostriatal synaptic plasticity. Nevertheless, it currently remains unclear whether and how αCaMKII plays a in the striatum-related neural disorders. To address the above issue, lentivirus-mediated short hairpin RNA (shRNA) was used to silence the expression of αCaMKII gene in the dorsal striatum of mice. As a consequence of down-regulation of dorsal striatal αCaMKII expression, we observed defective motor skill learning in accelerating rotarod and response learning in water cross maze. Furthermore, impaired corticostriatal basal transmission and long-term potentiation (LTP), which correlated with the deficits in dorsal striatum-related cognition, were also detected in the αCaMKII-shRNA mice. Consistent with the above results, αCaMKII-shRNA mice exhibited a remarkable decline in GluA1-Ser831 and GluA1-Ser845 phosphorylation levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and a decline in the expression levels ofN-methyl-d-aspartic acid receptor (NMDAR) subunits NR1, NR2A and NR2B. Taken together, αCaMKII down-regulation caused dorsal striatum-related cognitive disorders by inhibiting corticostriatal synaptic plasticity, which resulted from dysfunction of AMPARs and NMDARs. Our findings demonstrate for the first time an important role of αCaMKII in striatum-related neural disorders and provide further evidence for the proposition that corticostriatal LTP underlies aspects of dorsal striatum-related cognition.