A synthetic peptide ligand of neural cell adhesion molecule (NCAM) IgI domain prevents NCAM internalization and disrupts passive avoidance learning

The neural cell adhesion molecule (NCAM) mediates cell adhesion and signal transduction through trans-homophilic- and/or cis-heterophilic-binding mech anisms. 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 do main and the capability of inhibiting NCAM-mediated neurite outgrowth in vi tro. Intraventricular administration of a single 5 mu g bolus of C3 strongl y inhibited recall of a passive avoidance response in adult rats, when give n 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 amn esia was not observed until the 48-h recall time. The unique amnesic action of C3 during training could be related to disrupted NCAM internalization f ollowing training, In the 3-4-h posttraining period NCAM 180, the synapse-a ssociated isoform, was down-regulated in the hippocampal dentate gyrus, Thi s effect was mediated by ubiquitination and was prevented by C3 administrat ion during training. These findings indicate NCAM to be involved in both th e acquisition and consolidation of a passive avoidance response in the rat, Moreover, the study provides the first in vivo evidence for NCAM internali zation in learning and identifies a synthetic NCAM ligand capable of modula ting memory processes in vivo.