Restoration of synaptic plasticity and learning in young and aged NCAM-deficient mice by enhancing neurotransmission mediated by GluN2A-containing NMDA receptors.
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Restoration of synaptic plasticity and learning in young and aged NCAM-deficient mice by enhancing neurotransmission mediated by GluN2A-containing NMDA receptors. / Kochlamazashvili, Gaga; Bukalo, Olena; Senkov, Oleg; Salmen, Benedikt; Gerardy-Schahn, Rita; Engel, Andreas K.; Schachner, Melitta; Dityatev, Alexander.
in: J NEUROSCI, Jahrgang 32, Nr. 7, 7, 2012, S. 2263-2275.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Restoration of synaptic plasticity and learning in young and aged NCAM-deficient mice by enhancing neurotransmission mediated by GluN2A-containing NMDA receptors.
AU - Kochlamazashvili, Gaga
AU - Bukalo, Olena
AU - Senkov, Oleg
AU - Salmen, Benedikt
AU - Gerardy-Schahn, Rita
AU - Engel, Andreas K.
AU - Schachner, Melitta
AU - Dityatev, Alexander
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Age Factors
KW - Mice
KW - Mice, Knockout
KW - Neuronal Plasticity/physiology
KW - Synapses/metabolism
KW - Long-Term Potentiation/physiology
KW - Learning/physiology
KW - Aging/genetics/physiology
KW - Cycloserine/pharmacology
KW - Hippocampus/metabolism/pathology/physiology
KW - Neural Cell Adhesion Molecules/deficiency
KW - Neural Inhibition/physiology
KW - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/physiology
KW - Synaptic Transmission/drug effects/physiology
KW - Animals
KW - Male
KW - Age Factors
KW - Mice
KW - Mice, Knockout
KW - Neuronal Plasticity/physiology
KW - Synapses/metabolism
KW - Long-Term Potentiation/physiology
KW - Learning/physiology
KW - Aging/genetics/physiology
KW - Cycloserine/pharmacology
KW - Hippocampus/metabolism/pathology/physiology
KW - Neural Cell Adhesion Molecules/deficiency
KW - Neural Inhibition/physiology
KW - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/physiology
KW - Synaptic Transmission/drug effects/physiology
M3 - SCORING: Journal article
VL - 32
SP - 2263
EP - 2275
JO - J NEUROSCI
JF - J NEUROSCI
SN - 0270-6474
IS - 7
M1 - 7
ER -
