title: Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration.
abstract: 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.
authors: Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
authors: Satoru
authors: S
authors: Takahashi
authors: Toshio
authors: T
authors: Ohshima
authors: Motoyuki
authors: M
authors: Hirasawa
authors: Tej K
authors: TK
authors: Pareek
authors: Thomas H
authors: TH
authors: Bugge
authors: Alexei
authors: A
authors: Morozov
authors: Kenji
authors: K
authors: Fujieda
authors: Roscoe O
authors: RO
authors: Brady
authors: Ashok B
authors: AB
authors: Kulkarni
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency* / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology / Q000473:pathology*; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D009928:Organ Specificity; D016548:Prosencephalon / Q000196:embryology* / Q000201:enzymology* / Q000473:pathology; D016019:Survival Analysis; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D051360:Cyclin-Dependent Kinase 5; D010959:Tissue Plasminogen Activator