title: Restoration of synaptic plasticity and learning in young and aged NCAM-deficient mice by enhancing neurotransmission mediated by GluN2A-containing NMDA receptors.
abstract: Neural cell adhesion molecule (NCAM) is the predominant carrier of the unusual glycan polysialic acid (PSA). Deficits in PSA and/or NCAM expression cause impairments in hippocampal long-term potentiation and depression (LTP and LTD) and are associated with schizophrenia and aging. In this study, we show that impaired LTP in adult NCAM-deficient (NCAM(-/-)) mice is restored by increasing the activity of the NMDA subtype of glutamate receptor (GluN) through either reducing the extracellular Mg2+ concentration or applying d-cycloserine (DCS), a partial agonist of the GluN glycine binding site. Pharmacological inhibition of the GluN2A subtype reduced LTP to the same level in NCAM(-/-) and wild-type (NCAM(+/+)) littermate mice and abolished the rescue by DCS in NCAM(-/-) mice, suggesting that the effects of DCS are mainly mediated by GluN2A. The insufficient contribution of GluN to LTD in NCAM(-/-) mice was also compensated for by DCS. Furthermore, impaired contextual and cued fear conditioning levels were restored in NCAM(-/-) mice by administration of DCS before conditioning. In 12-month-old NCAM(-/-), but not NCAM(+/+) mice, there was a decline in LTP compared with 3-month-old mice that could be rescued by DCS. In 24-month-old mice of both genotypes, there was a reduction in LTP that could be fully restored by DCS in NCAM(+/+) mice but only partially restored in NCAM(-/-) mice. Thus, several deficiencies of NCAM(-/-) mice can be ameliorated by enhancing GluN2A-mediated neurotransmission with DCS.
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Gaga
authors.initials: G
authors.lastname: Kochlamazashvili
authors.forename: Olena
authors.initials: O
authors.lastname: Bukalo
authors.forename: Oleg
authors.initials: O
authors.lastname: Senkov
authors.forename: Benedikt
authors.initials: B
authors.lastname: Salmen
authors.forename: Rita
authors.initials: R
authors.lastname: Gerardy-Schahn
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Engel
authors.forename: Melitta
authors.initials: M
authors.lastname: Schachner
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D003523:Cycloserine / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019006:Neural Cell Adhesion Molecules / Q000172:deficiency*; D009433:Neural Inhibition / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D003523:Cycloserine; D019006:Neural Cell Adhesion Molecules; D016194:Receptors, N-Methyl-D-Aspartate