Fischer Andre, Sananbenesi Farahnaz, Pang Petti T, Lu Bai, Tsai Li-Huei
Harvard Medical School, Department of Pathology, Boston, Massachusetts 02115, USA.
Neuron. 2005 Dec 8;48(5):825-38. doi: 10.1016/j.neuron.2005.10.033.
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.
虽然细胞周期蛋白依赖性激酶5（Cdk5）的失调与神经退行性疾病有关，但其在突触可塑性和记忆中的精确作用仍不清楚。钙蛋白酶对Cdk5的调节亚基p35进行蛋白水解切割，导致截短的p25蛋白生成，从而引起Cdk5的过度激活。利用区域特异性和诱导性转基因小鼠，我们发现海马体中p25表达的短暂增加增强了长时程增强（LTP）并促进了海马体依赖性记忆。此外，p25表达增加了树突棘和突触的数量。重要的是，短暂表达p25随后抑制所实现的记忆增强并未导致神经退行性变。相反，p25的持续产生导致严重的认知缺陷，伴有突触和神经元丢失以及LTP受损。我们的数据表明p25在突触可塑性、突触形成、学习和记忆中发挥作用，并提供了一个模型，即可塑性因子的失调可能导致神经退行性变。
