Regulation of NMDA receptor Ca2+ signaling 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: 3.19). 12/2009; 37(Pt 6):1369-74. DOI: 10.1042/BST0371369
Source: PubMed


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.

Download full-text


Available from: Koichi Takeuchi
  • Source
    • "Several studies have shown that excessive activation of NMDA receptors, Ca 2+ fluxes into the post-synaptic cells, and generation of ROS/RNS subsequently causes neurodegeneration (Lau et al., 2009; Serrano-Pozo et al., 2011). Progressive neurodegeneration in AD brain is initially characterized by synaptic damage which is later accompanied by neuronal loss, especially in the hippocampus (Nobakht et al., 2011). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jun 2014 · Neurochemistry International
  • [Show abstract] [Hide abstract]
    ABSTRACT: This article investigates the problem of the inadequate and unequal nature of public toilet provision in Britain, where men are required under current statutory to be provided with almost twice more provision than women. The cultural and urological attitudes which legitimate this situation are investigated with reference to medical, sociological, town planning, building, and plumbing literature. It is found that “women's toilets” are a topic which does not quite fit into the jurisdiction of either medical or municipal authorities, although the issue should be seen as a key component of any preventative, public health programme, as was the case in Victorian and Edwardian times. But the need for better facilities is generally not taken seriously by the predominantly male committees who set provision standards. Recommendations are made for the amelioration of the situation by means of introducing mandatory enlightened standards operated through zoning compliance procedures within the town planning system.
    No preview · Article · Sep 1995 · Women s Studies International Forum
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two closely related peptides, which can activate protein kinase A (PKA). At least three receptors for PACAP and VIP have been identified. The PACAP-specific receptor, PAC1 receptor, exhibits a higher affinity for PACAP than VIP, whereas VIP receptors, VPAC1-R and VPAC2-R, have similar affinities for PACAP and VIP. Both PACAP/VIP and their cognate receptors are highly expressed in the brain, including the hippocampus. Recently, their roles in the regulation of synaptic transmission have begun to emerge. PACAP/VIP can signal through different pathways to regulate N-methyl-D: -aspartate (NMDA) receptors in CA1 pyramidal cells. The activation of VPAC1/2-Rs increases evoked NMDA currents via the cyclic AMP/PKA pathway. However, the activation of PAC1-R stimulates a PLC/PKC/Pyk2/Src signaling pathway to enhance NMDA receptor function in hippocampal neurons. Furthermore, different concentrations of PACAP induce different effects on the both α-amino-3-hydroxy-5-isoxazole-propionic acid-evoked current and basal synaptic transmission by activating different receptors. Their roles in learning and memory are also demonstrated using transgenic mice and pharmacological methods.
    No preview · Article · Apr 2010 · Journal of Molecular Neuroscience
Show more