Relationship Between GAP-43 Expression in the Dentate Gyrus and Synaptic Reorganization of Hippocampal Mossy Fibres in Rats Treated with Kainic Acid

Authors

  • C. Bendotti,

    Corresponding author
    1. Laboratory of Neuropharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea, 62, 20157 Milano, Italy
    • Caterina Bendotti, as above

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  • S. Baldessari,

    1. Laboratory of Neuropharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea, 62, 20157 Milano, Italy
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  • M. Pende,

    1. Laboratory of Neuropharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea, 62, 20157 Milano, Italy
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    • 2

      NIH, NICHD, Rockville Pike 9000, Bethesda, MD 20892, USA

  • T. Southgate,

    1. Laboratory of Neuropharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea, 62, 20157 Milano, Italy
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    • 3

      Molecular Medicine Unit, Dept. Medicine, University of Manchester, Room 1.302 Stopford Building, Oxford Road, Manchester, W13 9PT, UK

  • F. Guglielmetti,

    1. Laboratory of Neuropharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea, 62, 20157 Milano, Italy
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  • R. Samanin

    1. Laboratory of Neuropharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via Eritrea, 62, 20157 Milano, Italy
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Abstract

Kainic acid-induced seizures in adult rats produce neurodegeneration in the hippocampus followed by sprouting of the mossy fibres in the inner molecular layer of the dentate gyrus and changes in GAP-43 expression in the granule cells. In the present study we observed that 4 days after kainic acid injection a dense plexus of silver impregnated degenerating terminals detected by Gallyas's method and a decrease of GAP-43 immunostaining was observed in the inner molecular layer of the dentate gyrus indicating deafferentiation of this region. This was associated with the formation of an intense GAP-43 immunostained band in the supragranular layer. MK-801, a non-competitive inhibitor of the NMDA receptor, which partially inhibited the behavioural seizures induced by KA, also protected from the inner molecular layer deafferentation and markedly reduced the expression of GAP-43 mRNA in the granule cells and the intense GAP-43 immunostained band in the supragranular layer, suggesting a relationship among these events. Two months after kainic acid injection the intense supragranular GAP-43 positive band was no longer evident but the whole inner molecular layer appeared more labelled in association with the formation of the collateral sprouting of the mossy fibres in the inner molecular layer as detected by Timm's staining. These effects were also markedly reduced by the pretreatment with MK-801. Taken together, these experiments indicate for the first time a direct relationship between the increase of GAP-43 immunostaining in the inner molecular layer of the dentate gyrus and the collateral sprouting of mossy fibres in this district in response to kainic acid induced seizures. This further supports the hypothesis that the early induction of GAP-43 in granule cells may be one of the molecular mechanisms required for the synaptic reorganization of the mossy fibres.

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