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A Peptide Mimetic Targeting Trans-Homophilic NCAM Binding Sites Promotes Spatial Learning and Neural Plasticity in the Hippocampus

Kraev, I; Henneberger, C; Rossetti, C; Conboy, L; Kohler, LB; Fantin, M; Jennings, A; ... Sandi, C; + view all (2011) A Peptide Mimetic Targeting Trans-Homophilic NCAM Binding Sites Promotes Spatial Learning and Neural Plasticity in the Hippocampus. PLOS ONE , 6 (8) , Article e23433. 10.1371/journal.pone.0023433. Green open access

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Abstract

The key roles played by the neural cell adhesion molecule ( NCAM) in plasticity and cognition underscore this membrane protein as a relevant target to develop cognitive-enhancing drugs. However, NCAM is a structurally and functionally complex molecule with multiple domains engaged in a variety of actions, which raise the question as to which NCAM fragment should be targeted. Synthetic NCAM mimetic peptides that mimic NCAM sequences relevant to specific interactions allow identification of the most promising targets within NCAM. Recently, a decapeptide ligand of NCAM-plannexin, which mimics a homophilic trans-binding site in Ig2 and binds to Ig3-was developed as a tool for studying NCAM's trans-interactions. In this study, we investigated plannexin's ability to affect neural plasticity and memory formation. We found that plannexin facilitates neurite outgrowth in primary hippocampal neuronal cultures and improves spatial learning in rats, both under basal conditions and under conditions involving a deficit in a key plasticity-promoting posttranslational modification of NCAM, its polysialylation. We also found that plannexin enhances excitatory synaptic transmission in hippocampal area CA1, where it also increases the number of mushroom spines and the synaptic expression of the AMPAR subunits GluA1 and GluA2. Altogether, these findings provide compelling evidence that plannexin is an important facilitator of synaptic functional, structural and molecular plasticity in the hippocampal CA1 region, highlighting the fragment in NCAM's Ig3 module where plannexin binds as a novel target for the development of cognition-enhancing drugs.

Type: Article
Title: A Peptide Mimetic Targeting Trans-Homophilic NCAM Binding Sites Promotes Spatial Learning and Neural Plasticity in the Hippocampus
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0023433
Publisher version: http://dx.doi.org/10.1371/journal.pone.0023433
Language: English
Additional information: © 2011 Kraev et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported by grants from the EU 7th Framework Program (MemStick), the Swiss Society for Neuroscience (310000-120791; Sinergia CRSIK0-122697 and CRSIK0-122691) and by the Swiss Federal Institute for Technology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: CELL-ADHESION MOLECULE, LONG-TERM POTENTIATION, CENTRAL-NERVOUS-SYSTEM, POLYSIALIC ACID, DENTATE GYRUS, DENDRITIC SPINES, UP-REGULATION, COGNITIVE IMPAIRMENT, RECEPTOR TRAFFICKING, SYNAPTIC PLASTICITY
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
URI: https://discovery.ucl.ac.uk/id/eprint/1321888
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