Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation
Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation
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DOI：
10.1038/nn1914
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发表时间：
2007-07-01
影响因子：
25
通讯作者：
Bibb, James A.
中科院分区：
文献类型：
--
作者：
Hawasli, Ammar H.;Benavides, David R.;Bibb, James A.
学习伴随着神经元中突触后信号转导通路的调节。虽然神经元蛋白激酶细胞周期蛋白依赖性激酶5（Cdk5）已被牵连在认知障碍，其在学习中的作用已被模糊的围产期死亡的组成性基因敲除小鼠。在这里，我们报告，在成年小鼠大脑中的Cdk5的条件性敲除提高空间学习任务的性能，增强海马长时程增强和NMDA受体（NMDAR）介导的兴奋性突触后电流。Cdk5基因敲除小鼠的突触可塑性增强归因于NR2B降解减少，这导致NR2B亚基水平和通过含NR2B的NMDAR的电流升高。Cdk5通过直接与NR2B及其蛋白酶calpain相互作用而促进NR2B的降解。这些发现揭示了一个以前未知的机制，Cdk5促进钙蛋白酶介导的NR2B蛋白水解，并可能控制突触可塑性和学习。
Learning is accompanied by modulation of postsynaptic signal transduction pathways in neurons. Although the neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) has been implicated in cognitive disorders, its role in learning has been obscured by the perinatal lethality of constitutive knockout mice. Here we report that conditional knockout of Cdk5 in the adult mouse brain improved performance in spatial learning tasks and enhanced hippocampal long-term potentiation and NMDA receptor ( NMDAR)mediated excitatory postsynaptic currents. Enhanced synaptic plasticity in Cdk5 knockout mice was attributed to reduced NR2B degradation, which caused elevations in total, surface and synaptic NR2B subunit levels and current through NR2B-containing NMDARs. Cdk5 facilitated the degradation of NR2B by directly interacting with both it and its protease, calpain. These findings reveal a previously unknown mechanism by which Cdk5 facilitates calpain-mediated proteolysis of NR2B and may control synaptic plasticity and learning.