Regulation of hippocampal and behavioral excitability by cyclin-dependent kinase 5.
Regulation of hippocampal and behavioral excitability by cyclin-dependent kinase 5.
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DOI：
10.1371/journal.pone.0005808
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发表时间：
2009-06-04
期刊：
影响因子：
3.7
通讯作者：
Cooper DC
中科院分区：
文献类型：
--
作者：
Hawasli AH;Koovakkattu D;Hayashi K;Anderson AE;Powell CM;Sinton CM;Bibb JA;Cooper DC
细胞周期蛋白依赖性激酶5（Cdk 5）是一种脯氨酸导向的丝氨酸/苏氨酸激酶，其与学习、突触可塑性、神经传递和许多神经系统疾病有关。我们以前表明，条件性损失Cdk 5在成年小鼠增强海马的学习和可塑性，通过调节钙蛋白酶介导的N-甲基-D-天冬氨酸受体（NMDAR）降解。在本研究中，我们的特点是增强突触可塑性，并检查长期Cdk 5损失对成年小鼠海马兴奋性的影响。场兴奋性突触后电位（fEPSPs）从谢弗侧支CA 1海马（SC/CA 1）亚区揭示，Cdk 5的损失改变θ波阵发地形和增强强直后增强。由于Cdk 5控制NMDAR NR 2B亚基水平，我们通过测量NMDAR介导的fEPSP幅度和群体尖峰阈值来研究长期Cdk 5敲除对海马神经元兴奋性的影响。Cdk 5的长期丢失导致Mg 2+敏感电位增加，癫痫样活动和癫痫发作的阈值降低。进行生化分析以更好地了解Cdk 5在癫痫发作中的作用。在野生型动物中诱导癫痫发作导致Cdk 5激活辅因子p25的量升高。长期，但不是急性，Cdk 5的损失导致p25水平下降，这表明Cdk 5/p25可能被激活作为一种稳态机制，以减弱癫痫样活动。这些研究结果表明，Cdk 5调节突触可塑性，控制神经元和行为刺激诱导的兴奋性，并可能是认知和抗惊厥治疗的一个新的药理学靶点。
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that has been implicated in learning, synaptic plasticity, neurotransmission, and numerous neurological disorders. We previously showed that conditional loss of Cdk5 in adult mice enhanced hippocampal learning and plasticity via modulation of calpain-mediated N-methyl-D-aspartic acid receptor (NMDAR) degradation. In the present study, we characterize the enhanced synaptic plasticity and examine the effects of long-term Cdk5 loss on hippocampal excitability in adult mice. Field excitatory post-synaptic potentials (fEPSPs) from the Schaffer collateral CA1 subregion of the hippocampus (SC/CA1) reveal that loss of Cdk5 altered theta burst topography and enhanced post-tetanic potentiation. Since Cdk5 governs NMDAR NR2B subunit levels, we investigated the effects of long-term Cdk5 knockout on hippocampal neuronal excitability by measuring NMDAR-mediated fEPSP magnitudes and population-spike thresholds. Long-term loss of Cdk5 led to increased Mg2+-sensitive potentials and a lower threshold for epileptiform activity and seizures. Biochemical analyses were performed to better understand the role of Cdk5 in seizures. Induced-seizures in wild-type animals led to elevated amounts of p25, the Cdk5-activating cofactor. Long-term, but not acute, loss of Cdk5 led to decreased p25 levels, suggesting that Cdk5/p25 may be activated as a homeostatic mechanism to attenuate epileptiform activity. These findings indicate that Cdk5 regulates synaptic plasticity, controls neuronal and behavioral stimulus-induced excitability and may be a novel pharmacological target for cognitive and anticonvulsant therapies.
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