Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity.

Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Biochemical Society Transactions (Impact Factor: 2.59). 12/2009; 37(Pt 6):1369-74. DOI: 10.1042/BST0371369
Source: PubMed

ABSTRACT NMDARs (N-methyl-D-aspartate receptors) are critical for synaptic function throughout the CNS (central nervous system). NMDAR-mediated Ca(2+) influx is implicated in neuronal differentiation, neuronal migration, synaptogenesis, structural remodelling, long-lasting forms of synaptic plasticity and higher cognitive functions. NMDAR-mediated Ca(2+) signalling in dendritic spines is not static, but can be remodelled in a cell- and synapse-specific manner by NMDAR subunit composition, protein kinases and neuronal activity during development and in response to sensory experience. Recent evidence indicates that Ca(2+) permeability of neuronal NMDARs, NMDAR-mediated Ca(2+) signalling in spines and induction of NMDAR-dependent LTP (long-term potentiation) at hippocampal Schaffer collateral-CA1 synapses are under control of the cAMP/PKA (protein kinase A) signalling cascade. Thus, by enhancing Ca(2+) influx through NMDARs in spines, PKA can regulate the induction of LTP. An emerging concept is that activity-dependent regulation of NMDAR-mediated Ca(2+) signalling by PKA and by extracellular signals that modulate cAMP or protein phosphatases at synaptic sites provides a dynamic and potentially powerful mechanism for bi-directional regulation of synaptic efficacy and remodelling.

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    ABSTRACT: The N-methyl-D-aspartate (NMDA) receptor is a subtype of ionotropic glutamate receptor that is involved in synaptic mechanisms of learning and memory, and mediates excitotoxic neuronal injury. In this study, we tested the hypothesis that NMDA receptor subunit gene expression is altered in cortex and hippocampus of OKA induced memory impairment. Therefore in the present study, we checked the effect of OKA (ICV) on NMDA receptor regulation and synapse function. The memory function anomalies and synaptosomal calcium ion (Ca(2+)) level were increased in OKA treated rats brain; which was further protected by MK801 (0.05mg/kg. i.p.) treatment daily for 13 days. To elucidate the involvement of NMDA receptor, we estimated NR1, NR2A and NR2B (subunits) expression in rat brain. Results showed that expression of NR1 and NR2B were significantly increased, but expression of NR2A had no significant change in OKA treated rat brain. We also observed decrease in synapsin-1 mRNA and protein expression which indicates synapse dysfunction. In addition, we detected an increase in MDA and nitrite levels and a decrease in GSH level in synapse preparation which indicates synapse altered redox stress. Moreover, neuronal loss was also confirmed by nissl staining in periventricular cortex and hippocampus. Altered level of oxidative stress markers along with neuronal loss confirmed neurotoxicity. Further, MK801 treatment restored the level of NR1, NR2B and synapsin-1 expression, and protected from neuronal loss and synapse redox stress. In conclusion, Okadaic acid (OKA) induced expression of NR1 and NR2B deteriorates synapse function in rat brain which was confirmed by the neuroprotective effect of MK801.
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