Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration

Satoru Takahashi, Toshio Ohshima, Motoyuki Hirasawa, Tej K. Pareek, Thomas H. Bugge, Alexei Morozov, Kenji Fujieda, Roscoe O. Brady, Ashok B. Kulkarni

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    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 Cdk5 is 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.

    Original languageEnglish
    Pages (from-to)320-329
    Number of pages10
    JournalAmerican Journal of Pathology
    Volume176
    Issue number1
    DOIs
    Publication statusPublished - 2010 Jan

    Fingerprint

    Cyclin-Dependent Kinase 5
    Prosencephalon
    Group II Malformations of Cortical Development
    Seizures
    Knockout Mice
    Brain
    Inflammation
    Serine Proteases
    Tremor
    Tissue Plasminogen Activator
    Cause of Death
    Epilepsy
    Up-Regulation
    Neurons
    Growth

    ASJC Scopus subject areas

    • Pathology and Forensic Medicine

    Cite this

    Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration. / Takahashi, Satoru; Ohshima, Toshio; Hirasawa, Motoyuki; Pareek, Tej K.; Bugge, Thomas H.; Morozov, Alexei; Fujieda, Kenji; Brady, Roscoe O.; Kulkarni, Ashok B.

    In: American Journal of Pathology, Vol. 176, No. 1, 01.2010, p. 320-329.

    Research output: Contribution to journalArticle

    Takahashi, Satoru ; Ohshima, Toshio ; Hirasawa, Motoyuki ; Pareek, Tej K. ; Bugge, Thomas H. ; Morozov, Alexei ; Fujieda, Kenji ; Brady, Roscoe O. ; Kulkarni, Ashok B. / Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration. In: American Journal of Pathology. 2010 ; Vol. 176, No. 1. pp. 320-329.
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