Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration.
Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration.
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DOI：
10.2353/ajpath.2010.081158
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发表时间：
2010
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通讯作者：
Satoru Takahashi;T. Ohshima;Motoyuki Hirasawa;T. Pareek;T. Bugge;Alexei Morozov;K. Fujieda;R. Brady;A. Kulkarni
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作者：
Satoru Takahashi;T. Ohshima;Motoyuki Hirasawa;T. Pareek;T. Bugge;Alexei Morozov;K. Fujieda;R. Brady;A. Kulkarni
神经迁移障碍通常在药物治疗难治性癫痫患者中发现。已知长时间或反复发作可引起神经元死亡；然而，癫痫引起的神经元死亡的机制仍有待阐明。细胞周期蛋白依赖性激酶5（Cdk5）在脑发育中的重要作用已经在Cdk5（-/-）小鼠中得到证实，这些小鼠表现出神经元迁移缺陷和围产期死亡。在这里，我们通过产生Cdk5条件敲除小鼠来展示出生后大脑中Cdk5缺乏的后果，在这些小鼠中，Cdk5被选择性地从发育中的前脑神经元中消除。条件突变小鼠可以存活，但表现出复杂的神经功能缺陷，包括癫痫发作、震颤和生长迟缓。前脑不仅表现为分层破坏，还表现为神经退行性改变，伴有神经元丢失和小胶质细胞活化。神经退行性变化随着年龄的增长而进展，并伴有神经元组织型纤溶酶原激活剂（一种已知介导小胶质细胞激活的丝氨酸蛋白酶）的上调。因此，Cdk5条件敲除小鼠脑中的年龄依赖性神经变性引起了大量炎症反应。这些发现表明Cdk5在炎症中的重要作用，也提供了一个小鼠模型来研究炎症在神经元迁移障碍患者进行性认知能力下降的发病机制中的可能参与。
Neuronal migration disorders are often identified in patients with epilepsy refractory to medical treatment. The prolonged or repeated seizures are known to cause neuronal death; however, the mechanism underlying seizure-induced neuronal death remains to be elucidated. An essential role of cyclin-dependent kinase 5 (Cdk5) in brain development has been demonstrated in Cdk5(-/-) mice, which show neuronal migration defects and perinatal lethality. Here, we show the consequences of Cdk5 deficiency in the postnatal brain by generating Cdk5 conditional knockout mice, in which Cdk5is selectively eliminated from neurons in the developing forebrain. The conditional mutant mice were viable, but exhibited complex neurological deficits including seizures, tremors, and growth retardation. The forebrain not only showed disruption of layering, but also neurodegenerative changes accompanied by neuronal loss and microglial activation. The neurodegenerative changes progressed with age and were accompanied by up-regulation of the neuronal tissue-type plasminogen activator, a serine protease known to mediate microglial activation. Thus age-dependent neurodegeneration in the Cdk5 conditional knockout mouse brain invoked a massive inflammatory reaction. These findings indicate an important role of Cdk5 in inflammation, and also provide a mouse model to examine the possible involvement of inflammation in the pathogenesis of progressive cognitive decline in patients with neuronal migration disorders.