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 NMDAsubtype of glutamate receptor (GluN) through either reducing the extracellular Mg 2+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. © 2012 the authors.