CAS Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
Guangdong Province Key Laboratory of Brain Function and Disease, Faculty of Forensic Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
Neuropharmacology. 2018 Jan;128:207-220. doi: 10.1016/j.neuropharm.2017.10.015. Epub 2017 Oct 13.
Cyclin-dependent kinase 5 (Cdk5) acts as an essential modulator for neural development and neurological disorders. Here we show that Cdk5 plays a pivotal role in modulating GABAergic signaling and the maturation of visual system. In adult mouse primary visual cortex, Cdk5 formed complex with the GABA synthetic enzyme glutamate decarboxylase GAD67, but not with GAD65. In addition to enhancement in the surface level of NR2B-containing NMDA receptors, inhibition of Cdk5 reduced the protein levels of GADs and Otx2, while leaving intact the expression of vesicular GABA transporter and subunits of GABA or AMPA receptors. Whole-cell patch-clamp recording in layer II/III pyramidal neurons revealed a decrease in the frequency of miniature inhibitory postsynaptic current (mIPSC). Consequently, pharmacological inhibition and genetic knockdown of Cdk5 in adult mice led to a restoration of juvenile-like ocular dominance plasticity in vivo and long-term synaptic potential in layer II/III induced by white matter stimulation in vitro. Interestingly, we did not observe an alteration of perineuronal nets of extracellular matrix, but a reinstatement of the capability to evoke long-term depression at inhibitory synapses (iLTD), which depended on presynaptic endocannabinoid receptors and was a sign of the rejuvenated GABAergic synapses. Enhancement of GABA signaling by diazepam impeded ocular dominance plasticity rescued by Cdk5 inhibition. These results thus suggest that a physiological role of Cdk5 in visual cortex is to consolidate and stabilize neural circuits through controlling GABAergic signaling.
周期蛋白依赖性激酶 5（Cdk5）作为神经发育和神经紊乱的重要调节剂。在这里，我们表明 Cdk5 在调节 GABA 能信号和视觉系统成熟中起着关键作用。在成年小鼠初级视觉皮层中，Cdk5 与 GABA 合成酶谷氨酸脱羧酶 GAD67 形成复合物，但不与 GAD65 形成复合物。除了增强含有 NR2B 的 NMDA 受体的表面水平外，抑制 Cdk5 还降低了 GADs 和 Otx2 的蛋白水平，同时保持囊泡 GABA 转运体和 GABA 或 AMPA 受体亚单位的表达完整。在 II/III 层锥体神经元的全细胞膜片钳记录中，发现抑制 Cdk5 可降低微小抑制性突触后电流（mIPSC）的频率。因此，在成年小鼠中抑制 Cdk5 的药理学抑制和基因敲低导致了体内类似幼年的眼优势可塑性的恢复，以及体外白质刺激诱导的 II/III 层中的长时程突触电位。有趣的是，我们没有观察到细胞外基质的神经周细胞网络发生改变，而是重新建立了抑制性突触（iLTD）的长时程抑制能力，这依赖于突触前内源性大麻素受体，是 GABA 能突触年轻化的标志。地西泮增强 GABA 信号可阻止 Cdk5 抑制所挽救的眼优势可塑性。因此，这些结果表明 Cdk5 在视觉皮层中的生理作用是通过控制 GABA 能信号来巩固和稳定神经回路。
