Mita Naoki, He Xiaojuan, Sasamoto Kodai, Mishiba Tomohide, Ohshima Toshio
Laboratory for Molecular Brain Science, Department of Life Science and Medical Bioscience, Waseda University, Tokyo 162-8480, Japan.
Cereb Cortex. 2016 Mar;26(3):967-976. doi: 10.1093/cercor/bhu264. Epub 2014 Nov 17.
Cyclin-dependent kinase 5 (Cdk5) activity is dependent on its association with 1 of 2 neuron-specific activators, p35 or p39. Cdk5 and its activators play an important role in brain development as well as higher functions like synaptic plasticity, learning, and memory. Reduction in p35 was reported in postmortem schizophrenia brain, in which reduced dendritic spine density was observed. Previous in vitro experiments have shown that Cdk5 is involved in dendritic spine formation, although in vivo evidence is limited. We examined dendritic spine formation in inducible-p35 conditional knockout (p35 cKO); p39 KO mice. When we deleted the p35 gene either during early postnatal days or at adult stage, we observed reduced spine densities of layer V neurons in the cerebral cortex and CA1 pyramidal neurons in the hippocampus. We further generated CA1-specific p35 conditional knockout (CA1-p35 cKO) mice and also CA1-p35 cKO; p39 KO mice in which have specific deletion of p35 in the CA1 region of hippocampus. We found a greater reduction in spine densities in CA1 pyramidal neurons in CA1-p35 cKO; p39 KO mice than in CA1-p35 cKO mice. These results indicate that dendritic spine formation and neuronal maintenance are dependent on Cdk5 activity.
细胞周期蛋白依赖性激酶5（Cdk5）的活性取决于它与两种神经元特异性激活剂之一p35或p39的结合。Cdk5及其激活剂在大脑发育以及诸如突触可塑性、学习和记忆等高级功能中发挥着重要作用。据报道，在精神分裂症患者的尸检大脑中p35减少，其中观察到树突棘密度降低。先前的体外实验表明Cdk5参与树突棘的形成，尽管体内证据有限。我们研究了诱导型p35条件性敲除（p35 cKO）；p39敲除小鼠中的树突棘形成。当我们在出生后早期或成年阶段删除p35基因时，我们观察到大脑皮层V层神经元和海马体CA1锥体神经元的棘密度降低。我们进一步生成了CA1特异性p35条件性敲除（CA1-p35 cKO）小鼠以及在海马体CA1区域特异性缺失p35的CA1-p35 cKO；p39敲除小鼠。我们发现，与CA1-p35 cKO小鼠相比，CA1-p35 cKO；p39敲除小鼠的CA1锥体神经元的棘密度降低得更多。这些结果表明，树突棘的形成和神经元的维持依赖于Cdk5的活性。
