Hawasli Ammar H, Benavides David R, Nguyen Chan, Kansy Janice W, Hayashi Kanehiro, Chambon Pierre, Greengard Paul, Powell Craig M, Cooper Donald C, Bibb James A
Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390, USA.
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, Centre Universitaire de Strasbourg, France.
Nat Neurosci. 2007 Jul;10(7):880-886. doi: 10.1038/nn1914. Epub 2007 May 27.
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.
学习过程伴随着神经元中突触后信号转导通路的调节。尽管神经元蛋白激酶细胞周期蛋白依赖性激酶5（Cdk5）与认知障碍有关，但其在学习中的作用因组成型敲除小鼠的围产期致死率而变得模糊不清。在此我们报告，成年小鼠大脑中Cdk5的条件性敲除改善了空间学习任务中的表现，并增强了海马体长期增强效应以及NMDA受体（NMDAR）介导的兴奋性突触后电流。Cdk5基因敲除小鼠中增强的突触可塑性归因于NR2B降解减少，这导致了总的、表面的和突触的NR2B亚基水平升高以及通过含NR2B的NMDAR的电流增加。Cdk5通过直接与NR2B及其蛋白酶钙蛋白酶相互作用，促进了NR2B的降解。这些发现揭示了一种此前未知的机制，通过该机制Cdk5促进了钙蛋白酶介导的NR2B蛋白水解，并且可能控制突触可塑性和学习。
