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      NMDA Receptor Function During Senescence: Implication on Cognitive Performance

      review-article
      Frontiers in Neuroscience
      Frontiers Media S.A.
      aging, hippocampus, oxidative stress, NMDA receptor, GluN2A, GluN2B, learning, spatial memory

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          Abstract

          N-methyl-D-aspartate (NMDA) receptors, a family of L-glutamate receptors, play an important role in learning and memory, and are critical for spatial memory. These receptors are tetrameric ion channels composed of a family of related subunits. One of the hallmarks of the aging human population is a decline in cognitive function; studies in the past couple of years have demonstrated deterioration in NMDA receptor subunit expression and function with advancing age. However, a direct relationship between impaired memory function and a decline in NMDA receptors is still ambiguous. Recent studies indicate a link between an age-associated NMDA receptor hypofunction and memory impairment and provide evidence that age-associated enhanced oxidative stress might be contributing to the alterations associated with senescence. However, clear evidence is still deficient in demonstrating the underlying mechanisms and a relationship between age-associated impaired cognitive faculties and NMDA receptor hypofunction. The current review intends to present an overview of the research findings regarding changes in expression of various NMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function.

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          Most cited references217

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          Synaptic plasticity and memory: an evaluation of the hypothesis.

          Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.
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            Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

            An in situ study of mRNAs encoding NMDA receptor subunits in the developing rat CNS revealed that, at all stages, the NR1 gene is expressed in virtually all neurons, whereas the four NR2 transcripts display distinct expression patterns. NR2B and NR2D mRNAs occur prenatally, whereas NR2A and NR2C mRNAs are first detected near birth. All transcripts except NR2D peak around P20. NR2D mRNA, present mainly in midbrain structures, peaks around P7 and thereafter decreases to adult levels. Postnatally, NR2B and NR2C transcript levels change in opposite directions in the cerebellar internal granule cell layer. In the adult hippocampus, NR2A and NR2B mRNAs are prominent in CA1 and CA3 pyramidal cells, but NR2C and NR2D mRNAs occur in different subsets of interneurons. Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants. Thus, the distinct expression profiles and functional properties of NR2 subunits provide a basis for NMDA channel heterogeneity in the brain.
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              The glutamate receptor ion channels.

                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                16 December 2015
                2015
                : 9
                : 473
                Affiliations
                Department of Neuroscience, Evelyn F. and William L. McKnight Brain Institute, University of Florida Gainesville, FL, USA
                Author notes

                Edited by: Con Stough, Swinburne University of Technology, Australia

                Reviewed by: Muzamil Ahmad, Indian Institute of Integrative Medicine, India; Luca Ferraro, University of Ferrara, Italy; Boyer D. Winters, University of Guelph, Canada

                *Correspondence: Ashok Kumar kash@ 123456ufl.edu

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2015.00473
                4679982
                26732087
                bdc9ca24-d0e7-4115-8742-e4d5a0e03f87
                Copyright © 2015 Kumar.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 September 2015
                : 25 November 2015
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 234, Pages: 15, Words: 13091
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: AG037984
                Award ID: AG036800
                Award ID: AG049711
                Award ID: NS040389
                Funded by: Evelyn F. McKnight Brain Research Foundation 10.13039/100007049
                Categories
                Pharmacology
                Review

                Neurosciences
                aging,hippocampus,oxidative stress,nmda receptor,glun2a,glun2b,learning,spatial memory
                Neurosciences
                aging, hippocampus, oxidative stress, nmda receptor, glun2a, glun2b, learning, spatial memory

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