title: Involvement of cyclin-dependent kinase-5 in the kainic acid-mediated degeneration of glutamatergic synapses in the rat hippocampus.
abstract: Increased levels of glutamate causing excitotoxic damage accompany neurological disorders such as ischemia/stroke, epilepsy and some neurodegenerative diseases. Cyclin-dependent kinase-5 (Cdk5) is important for synaptic plasticity and is deregulated in neurodegenerative diseases. However, the mechanisms by which kainic acid (KA)-induced excitotoxic damage involves Cdk5 in neuronal injury are not fully understood. In this work, we have thus studied involvement of Cdk5 in the KA-mediated degeneration of glutamatergic synapses in the rat hippocampus. KA induced degeneration of mossy fiber synapses and decreased glutamate receptor (GluR)6/7 and post-synaptic density protein 95 (PSD95) levels in rat hippocampus in vivo after intraventricular injection of KA. KA also increased the cleavage of Cdk5 regulatory protein p35, and Cdk5 phosphorylation in the hippocampus at 12 h after treatment. Studies with hippocampal neurons in vitro showed a rapid decline in GluR6/7 and PSD95 levels after KA treatment with the breakdown of p35 protein and phosphorylation of Cdk5. These changes depended on an increase in calcium as shown by the chelators 1,2-bis(o-aminophenoxy)ethane-N,N,N ',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) and glycol-bis (2-aminoethylether)-N,N,N ',N '-tetra-acetic acid. Inhibition of Cdk5 using roscovitine or employing dominant-negative Cdk5 and Cdk5 silencing RNA constructs counteracted the decreases in GluR6/7 and PSD95 levels induced by KA in hippocampal neurons. The dominant-negative Cdk5 was also able to decrease neuronal degeneration induced by KA in cultured neurons. The results show that Cdk5 is essentially involved in the KA-mediated alterations in synaptic proteins and in cell degeneration in hippocampal neurons after an excitotoxic injury. Inhibition of pathways activated by Cdk5 may be beneficial for treatment of synaptic degeneration and excitotoxicity observed in various brain diseases.
authors: Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, Helsinki, Finland.
authors: Noora
authors: N
authors: Putkonen
authors: Jyrki P
authors: JP
authors: Kukkonen
authors: Guiseppa
authors: G
authors: Mudo
authors: Jaana
authors: J
authors: Putula
authors: Natale
authors: N
authors: Belluardo
authors: Dan
authors: D
authors: Lindholm
authors: Laura
authors: L
authors: Korhonen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000097806:GluK2 Kainate Receptor; D000097808:GluK3 Kainate Receptor
chemical_list: D002118:Calcium; D002154:Calpain; D051360:Cyclin-Dependent Kinase 5; D000076122:Disks Large Homolog 4 Protein; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; D007608:Kainic Acid; D008565:Membrane Proteins; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; D000097808:GluK3 Kainate Receptor; C501449:Dlg4 protein, rat