Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory
Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory
复制标题
DOI：
10.1016/j.neuron.2005.10.033
复制
发表时间：
2005-12-08
期刊：
影响因子：
16.2
通讯作者：
Tsai, LH
中科院分区：
文献类型：
--
作者：
Fischer, A;Sananbenesi, F;Tsai, LH
尽管细胞周期蛋白依赖性激酶5(CDK5)的失控与神经退行性疾病有关，但其在突触可塑性和记忆中的确切作用仍不清楚。钙蛋白酶对CDK5的调节亚基p35进行蛋白水解性切割，导致截短的p25蛋白的产生，从而导致CDK5的过度激活。利用区域特定和可诱导的转基因小鼠，我们表明，海马区p25表达的瞬时增加增强了长时程增强(LTP)，并促进了海马区依赖的记忆。此外，p25的表达增加了树突棘和突触的数量。重要的是，通过瞬时表达p25并随后抑制其实现的增强记忆并不会导致神经退化。相比之下，p25的长时间产生会导致严重的认知障碍，并伴随着突触和神经元的丢失以及LTP的受损。我们的数据表明p25在突触可塑性、突触发生、学习和记忆中发挥作用，并提供了一个模型，通过该模型，可塑性因子的去调节可以促进神经退化。
While deregulation of cyclin-dependent kinase 5 (Cdk5) has been implicated in neurodegenerative diseases, its precise role in synaptic plasticity and memory remains elusive. Proteolytic cleavage of p35, a regulatory subunit of Cdk5, by calpain results in the generation of the truncated p25 protein, which causes hyperactivation of Cdk5. Using region-specific and inducible transgenic mice, we show that transiently increased p25 expression in the hippocampus enhanced long-term potentiation (LTP) and facilitated hippocampus-dependent memory. Moreover, p25 expression increased the number of dendritic spines and synapses. Importantly, enhanced memory achieved by a transient expression of p25 followed by its repression did not cause neurodegeneration. In contrast, prolonged p25 production caused severe cognitive deficits, which were accompanied by synaptic and neuronal loss and impaired LTP. Our data suggest a role for p25 in synaptic plasticity, synaptogenesis, learning, and memory and provide a model whereby deregulation of a plasticity factor can contribute to neurodegeneration.