A Synthetic Peptide Ligand of Neural Cell Adhesion Molecule (NCAM) IgI Domain Prevents NCAM Internalization and Disrupts Passive Avoidance Learning

Authors

  • Andrew G. Foley,

    1. Department of Pharmacology, Conway Institute, University College Dublin, Dublin, Ireland*Protein Laboratory, Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Barbara P. Hartz,

    1. Department of Pharmacology, Conway Institute, University College Dublin, Dublin, Ireland*Protein Laboratory, Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • * Helen C. Gallagher,

    1. Department of Pharmacology, Conway Institute, University College Dublin, Dublin, Ireland*Protein Laboratory, Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Lars C. B. Rønn,

    1. Department of Pharmacology, Conway Institute, University College Dublin, Dublin, Ireland*Protein Laboratory, Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Vladimir Berezin,

    1. Department of Pharmacology, Conway Institute, University College Dublin, Dublin, Ireland*Protein Laboratory, Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • * Elisabeth Bock,

    1. Department of Pharmacology, Conway Institute, University College Dublin, Dublin, Ireland*Protein Laboratory, Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • and * Ciaran M. Regan

    1. Department of Pharmacology, Conway Institute, University College Dublin, Dublin, Ireland*Protein Laboratory, Panum Institute, University of Copenhagen, Copenhagen, Denmark
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  • Lippincott Williams & Wilkins, Inc., Philadelphia

  • Abbreviations used: C3d, dendrimer of C3 peptides; NCAM, neural cell adhesion molecule; PAGE, polyacrylamide gel electrophoresis; SDS, sodium dodecyl sulphate; TBS-T, 10 mM Tris-HCl, 150 mM NaCl, and 0.5% (vol/vol) Tween-20 (pH 7.4).

Address correspondence and reprint requests to Prof. C. M. Regan at Department of Pharmacology, University College Dublin, Belfield, Dublin 4, Ireland. E-mail: Ciaran.Regan@ucd.ie

Abstract

Abstract: The neural cell adhesion molecule (NCAM) mediates cell adhesion and signal transduction through trans-homophilic- and/or cis-heterophilic-binding mechanisms. Intraventricular infusions of anti-NCAM have revealed a functional requirement of NCAM for the consolidation of memory in rats and chicks in a specific interval 6-8 h after training. We have now extended these studies to a synthetic peptide ligand of NCAM (C3) with an affinity for the IgI domain and the capability of inhibiting NCAM-mediated neurite outgrowth in vitro. Intraventricular administration of a single 5 μg bolus of C3 strongly inhibited recall of a passive avoidance response in adult rats, when given during training or in the 6-8-h posttraining period. The effect of C3 on memory consolidation was similar to that obtained with anti-NCAM as the amnesia was not observed until the 48-h recall time. The unique amnesic action of C3 during training could be related to disrupted NCAM internalization following training. In the 3-4-h posttraining period NCAM 180, the synapse-associated isoform, was down-regulated in the hippocampal dentate gyrus. This effect was mediated by ubiquitination and was prevented by C3 administration during training. These findings indicate NCAM to be involved in both the acquisition and consolidation of a passive avoidance response in the rat. Moreover, the study provides the first in vivo evidence for NCAM internalization in learning and identifies a synthetic NCAM ligand capable of modulating memory processes in vivo.

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