The Journal of Neuroscience, August 15, 2001, 21(16):6086-6094
Cyclin-Dependent Kinase 4 and Cyclin D1 Are Required for
Excitotoxin-Induced Neuronal Cell Death In Vivo
Hidetoshi
Ino and
Tanemichi
Chiba
Department of Neurobiology (C1), Graduate School of Medicine, Chiba
University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
Systemic administration of the glutamic acid analog kainic acid
(KA) causes neuronal cell death in brain-vulnerable regions, such as
the piriform cortex, hippocampus, and amygdala in rats. We investigated
the relationship between the KA-induced neuronal apoptosis and
expression of cyclin-dependent kinase 4 (CDK4) and cyclin D1, key
regulators of cell cycle progression. Expression of CDK4 and cyclin D1
was upregulated in neurons of the rat piriform cortex and amygdala 1-3
d after KA administration in vivo. CDK4 and cyclin D1
proteins were induced in the cytoplasm and nuclei of neurons, with a
concomitant increase of CDK4- and cyclin D1-positive microglia in the
affected areas. Continuous infusion of 100 µM CDK4 or
cyclin D1 antisense oligonucleotides into the lateral ventricle using
mini-osmotic pumps suppressed the excitotoxin-induced neuronal cell
death in the piriform cortex and basolateral amygdaloid nucleus,
whereas sense oligonucleotides exhibited no such effect. Although KA
administration causes prolonged c-Fos expression in the vulnerable
regions that preceded the induction of neuronal apoptosis, the CDK4 or
cyclin D1 antisense oligonucleotides exhibited no suppressive effect on
c-Fos levels. Our results suggest that CDK4 and cyclin D1 are essential
for KA-induced neuronal apoptosis in vivo.
Key words:
CDK4; cyclin D1; cyclin-dependent kinases; cyclins; neuronal cell death; kainate; phosphorothioate antisense
oligonucleotides
Copyright © 2001 Society for Neuroscience 0270-6474/01/21166086-09$05.00/0
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