A peptide mimetic targeting trans-homophilic NCAM binding sites promotes spatial learning and neural plasticity in the hippocampus

• Published in: PloS one 2011-08, Vol.6 (8), p.e23433
• Main Authors: Kraev, Igor, Henneberger, Christian, Rossetti, Clara, Conboy, Lisa, Kohler, Lene B, Fantin, Martina, Jennings, Alistair, Venero, Cesar, Popov, Victor, Rusakov, Dmitri, Stewart, Michael G, Bock, Elisabeth, Berezin, Vladimir, Sandi, Carmen
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Axonogenesis; Binding Sites; Biology; Biomarkers - metabolism; Brain; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell Survival - drug effects; Cells, Cultured; Cognition; Cognitive ability; Dendritic spines; Dendritic Spines - drug effects; Dendritic Spines - metabolism; Drug development; Drugs; Epilepsy; Functional plasticity; Genetics; Glycoside Hydrolases - metabolism; Hippocampal plasticity; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiology; Hippocampus - ultrastructure; Laboratories; Learning - drug effects; Life sciences; Male; Maze Learning - drug effects; Membrane proteins; Mice; Models, Molecular; Morphology; Neural cell adhesion molecule; Neural Cell Adhesion Molecules - metabolism; Neurites - drug effects; Neurites - metabolism; Neurology; Neuronal Plasticity - drug effects; Neuroplasticity; Neurosciences; Oligopeptides - administration & dosage; Oligopeptides - chemistry; Oligopeptides - pharmacology; Peptides; Pharmacology; Plasticity (neural); Polysialylation; Protein Subunits - metabolism; Proteins; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Glutamate - metabolism; Rodents; Sialic Acids - metabolism; Spatial discrimination learning; Spatial memory; Structure-function relationships; Synaptic plasticity; Synaptic transmission; Synaptic Transmission - drug effects; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023433

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.