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Involvement of cyclin-dependent kinase-5 in the kainic acid-mediated degeneration of glutamatergic synapses in the rat hippocampus

Authors

  • Noora Putkonen,

    1. Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland
    2. Minerva Medical Research Institute, Biomedicum-2 Helsinki, Helsinki, Finland
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  • Jyrki P. Kukkonen,

    1. Minerva Medical Research Institute, Biomedicum-2 Helsinki, Helsinki, Finland
    2. Unit of Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
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  • Guiseppa Mudo,

    1. Division of Human Physiology, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
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  • Jaana Putula,

    1. Unit of Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland
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  • Natale Belluardo,

    1. Division of Human Physiology, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy
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  • Dan Lindholm,

    1. Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland
    2. Minerva Medical Research Institute, Biomedicum-2 Helsinki, Helsinki, Finland
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  • Laura Korhonen

    1. Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Haartmaninkatu 8, FIN-00290 Helsinki, Finland
    2. Minerva Medical Research Institute, Biomedicum-2 Helsinki, Helsinki, Finland
    3. Division of Child Psychiatry, Helsinki University Central Hospital, Helsinki, Finland
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L. Korhonen, 1Institute of Biomedicine/Biochemistry, as above.
E-mail: laura.t.korhonen@helsinki.fi

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.

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