title: Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement.
abstract: Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL) from the neural cell adhesion molecule (NCAM) that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP). Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer.
authors.affiliation: Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid, Madrid, Spain. sknafo@cbm.uam.es
authors.forename: Shira
authors.initials: S
authors.lastname: Knafo
authors.forename: César
authors.initials: C
authors.lastname: Venero
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Puelles
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Pereda-Peréz
authors.forename: Ana
authors.initials: A
authors.lastname: Franco
authors.forename: Carmen
authors.initials: C
authors.lastname: Sandi
authors.forename: Luz M
authors.initials: LM
authors.lastname: Suárez
authors.forename: José M
authors.initials: JM
authors.lastname: Solís
authors.forename: Lidia
authors.initials: L
authors.lastname: Alonso-Nanclares
authors.forename: Eduardo D
authors.initials: ED
authors.lastname: Martín
authors.forename: Paula
authors.initials: P
authors.lastname: Merino-Serrais
authors.forename: Erika
authors.initials: E
authors.lastname: Borcel
authors.forename: Shizhong
authors.initials: S
authors.lastname: Li
authors.forename: Yongshuo
authors.initials: Y
authors.lastname: Chen
authors.forename: Juncal
authors.initials: J
authors.lastname: Gonzalez-Soriano
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bock
authors.forename: Javier
authors.initials: J
authors.lastname: Defelipe
authors.forename: José A
authors.initials: JA
authors.lastname: Esteban
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D019006:Neural Cell Adhesion Molecules / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
chemical_list: C488618:NCAM protein (681-695), human; D019006:Neural Cell Adhesion Molecules; D018091:Receptors, AMPA; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2