Kochlamazashvili, Gaga, Bukalo, Olena, Senkov, Oleg, Salmen, Benedikt, Gerardy-SChahn, Rita, Engel, Andreas, Schachner, Melitta and Dityatev, Alexander (2012) Restoration of synaptic plasticity and learning in young and aged NCAM-deficient mice via elevation of neurotransmission mediated by the GluN2A-containing NMDA receptors. J Neuroscience.

Abstract

The neural cell adhesion molecule NCAM is the predominant carrier of the unusual polysialic
acid (PSA). Deficits in PSA and/or NCAM expression cause impairments in hippocampal longterm
potentiation and depression (LTP and LTD), and are associated with schizophrenia and
aging. Here, we show that impaired LTP in adult NCAM deficient (NCAM-/-) mice is restored
by increasing the activity of the NMDA subtype of glutamate receptors (GluN) by either
elevation of extracellular Ca2+ and reduction of extracellular Mg2+ concentrations, or by Dcycloserine
(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
DSC are mediated by GluN2A. In NCAM-/- and NCAM+/+ mice, LTD was impaired in the
presence of GluN2A or GluN2B antagonists, suggesting that both GluN2A and GluN2B are
required for this form of plasticity. Remarkably, insufficient contribution of GluN to LTD in
NCAM-/- mice was compensated by DCS. Furthermore, impaired contextual and cued fear
conditioning was restored in NCAM-/- mice by administration of DCS before conditioning. In 1-
year-old NCAM+/+ mice, LTP matched that of 3-month-old mice, but was further reduced in 1-
year-old NCAM-/- mice when compared to 3-month-old NCAM-/- mice. DCS fully restored LTP
at this age and partially rescued LTP in 2-year-old NCAM-/- mice. Thus, several deficiencies in
synaptic plasticity and learning of NCAM-/- mice can be abrogated by enhancement of GluN2Amediated
neurotransmission.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/5337