Wang Qi, Yin Pengcheng, Yu Bin, Zhao Zheng, Richter-Levin Gal, Yu Lu, Cao Xiaohua
Key Laboratory of Brain Functional Genomics, MOE & STCSM, East China Normal University, Shanghai 200062, China.
"Sagol" Department of Neurobiology, University of Haifa, Haifa 31905, Israel.
Exp Neurol. 2017 Dec;298(Pt A):112-121. doi: 10.1016/j.expneurol.2017.09.004. Epub 2017 Sep 8.
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 of N-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.
α钙调蛋白依赖性蛋白激酶II（αCaMKII）是一种丝氨酸/苏氨酸蛋白激酶，在背侧纹状体中大量表达，并且高度参与皮质纹状体突触可塑性。然而，目前尚不清楚αCaMKII是否以及如何在纹状体相关的神经疾病中发挥作用。为了解决上述问题，使用慢病毒介导的短发夹RNA（shRNA）来沉默小鼠背侧纹状体中αCaMKII基因的表达。由于背侧纹状体αCaMKII表达下调，我们观察到加速转棒实验中的运动技能学习缺陷以及水迷宫实验中的反应学习缺陷。此外，在αCaMKII-shRNA小鼠中还检测到皮质纹状体基础传递和长时程增强（LTP）受损，这与背侧纹状体相关认知缺陷相关。与上述结果一致，αCaMKII-shRNA小鼠的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的GluA1-Ser831和GluA1-Ser845磷酸化水平显著下降，N-甲基-D-天冬氨酸受体（NMDAR）亚基NR1、NR2A和NR2B的表达水平也下降。综上所述，αCaMKII下调通过抑制皮质纹状体突触可塑性导致背侧纹状体相关认知障碍，这是由AMPAR和NMDAR功能障碍引起的。我们的研究首次证明了αCaMKII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方面的基础这一观点提供了进一步的证据。
