Impairment of hippocampal long-term depression and defective spatial learning and memory in p35-/- mice
Impairment of hippocampal long-term depression and defective spatial learning and memory in p35-/- mice
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DOI：
10.1111/j.1471-4159.2005.03233.x
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发表时间：
2005-08-01
影响因子：
4.7
通讯作者：
Mikoshiba, K
中科院分区：
文献类型：
--
作者：
Ohshima, T;Ogura, H;Mikoshiba, K
CDK5(细胞周期蛋白依赖性激酶5)的活性依赖于与两个神经元特异性激活物p35或p39之一的联系。CDK5基因缺失会导致围产儿死亡，并在皮质生成和神经元定位方面存在严重缺陷。P35(-/-)小鼠有较轻微的组织学异常，可以存活。尽管大量证据表明CDK5与突触可塑性有关，但它在学习和记忆中的作用尚未通过突变小鼠模型进行评估。我们在这里报告了p35(-/-)小鼠在空间学习和记忆方面的缺陷。仔细检查海马区回路，发现CA1区锥体细胞存在细微的组织学缺陷。此外，p35(-/-)小鼠表现出Schaeffer侧支CA1通路中长期抑制和长期增强的减弱。此外，在4周龄的小鼠中，蛋白磷酸酶抑制物-1的CDK5依赖的磷酸化状态由于P39水平的增加而增加，P39与抑制物-1和CDK5共同定位在细胞质中。这些结果表明，依赖p35的CDK5活性对学习和突触可塑性是重要的。由于p39的代偿表达，p35的缺失可能会改变CDK5的底物特异性。
Cdk5 (cyclin-dependent kinase 5) activity is dependent upon association with one of two neuron-specific activators, p35 or p39. Genetic deletion of Cdk5 causes perinatal lethality with severe defects in corticogenesis and neuronal positioning. p35(-/-) mice are viable with milder histological abnormalities. Although substantial evidence implicates Cdk5 in synaptic plasticity, its role in learning and memory has not been evaluated using mutant mouse models. We report here that p35(-/-) mice have deficiencies in spatial learning and memory. Close examination of hippocampal circuitry revealed subtle histological defects in CA1 pyramidal cells. Furthermore, p35(-/-) mice exhibit impaired long-term depression and depotentiation of long-term potentiation in the Schaeffer collateral CA1 pathway. Moreover, the Cdk5-dependent phosphorylation state of protein phosphatase inhibitor-1 was increased in 4-week-old mice due to increased levels of p39, which co-localized with inhibitor-1 and Cdk5 in the cytoplasm. These results demonstrate that p35-dependent Cdk5 activity is important to learning and synaptic plasticity. Deletion of p35 may shift the substrate specificity of Cdk5 due to compensatory expression of p39.