Diversity in NMDA Receptor Composition Many Regulators, Many Consequences
TL;DR: The authors summarize the recent advances in the identification of NMDAR subunit-specific regulatory mechanisms and some of the molecular mechanisms underlying this GluN2 subunit switch have been recently identified.
Abstract: N-methyl-D-aspartate receptors (NMDARs) are a subtype of ionotropic glutamate receptor, which play a central role in learning, memory, and synaptic development. NMDARs are assembled as tetramers composed of two GluN1 subunits and two GluN2 or GluN3 subunits. Although NMDARs are widely expressed throughout the central nervous system, their number, localization, and subunit composition are strictly regulated and differ in a cell- and synapse-specific manner. The brain area, developmental stage, and level of synaptic activity are some of the factors that regulate NMDARs. Molecular mechanisms that control subunit-specific NMDAR function include developmental regulation of subunit transcription/translation, differential trafficking through the secretory pathway, posttranscriptional modifications such as phosphorylation, and protein-protein interactions. The GluN2A and GluN2B subunits are highly expressed in cortex and hippocampus and confer many of the distinct properties on endogenous NMDARs. Importantly, the synaptic NMDAR subunit composition changes from predominantly GluN2B-containing to GluN2A-containing NMDARs during synaptic maturation and in response to activity and experience. Some of the molecular mechanisms underlying this GluN2 subunit switch have been recently identified. In addition, the balance between synaptic and extrasynaptic NMDARs is altered in several neuronal disorders. Here, the authors summarize the recent advances in the identification of NMDAR subunit-specific regulatory mechanisms.
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TL;DR: The effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders are reviewed and could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.
Abstract: NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit composition of NMDARs is plastic, resulting in a large number of receptor subtypes. As each receptor subtype has distinct biophysical, pharmacological and signalling properties, there is great interest in determining whether individual subtypes carry out specific functions in the CNS in both normal and pathological conditions. Here, we review the effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission.
1,918 citations
TL;DR: Evidence both supporting and refuting the localization hypothesis of NMDAR function is reviewed and the role of N MDAR localization in disorders of the nervous system is discussed, particularly in Alzheimer disease and Huntington disease.
422 citations
Centre national de la recherche scientifique1, Karolinska Institutet2, Lund University3, Columbia University4, University of British Columbia5, University of Cagliari6, Vanderbilt University Medical Center7, Oklahoma State University Center for Health Sciences8, University of Ferrara9, University of Milan10, Michigan State University11, Toronto Western Hospital12
TL;DR: The present review attempts to provide an overview of the current understanding of dyskinesia and other L-dopa-induced dysfunctions to help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.
365 citations
TL;DR: The importance of recent genetic findings on the different mechanisms of structural plasticity are discussed and it is proposed that these converge on shared pathways that can be targeted with novel therapeutics.
Abstract: The structure of neuronal circuits that subserve cognitive functions in the brain is shaped and refined throughout development and into adulthood. Evidence from human and animal studies suggests that the cellular and synaptic substrates of these circuits are atypical in neuropsychiatric disorders, indicating that altered structural plasticity may be an important part of the disease biology. Advances in genetics have redefined our understanding of neuropsychiatric disorders and have revealed a spectrum of risk factors that impact pathways known to influence structural plasticity. In this Review, we discuss the importance of recent genetic findings on the different mechanisms of structural plasticity and propose that these converge on shared pathways that can be targeted with novel therapeutics.
325 citations
TL;DR: The relationship between NMDA receptor structure and function is reviewed with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.
Abstract: NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.
316 citations
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TL;DR: Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.
Abstract: In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.
3,941 citations
"Diversity in NMDA Receptor Composit..." refers background in this paper
...Importantly, it has been described that Abeta oligomers are able to bind with specificity to excitatory synapses and alter synaptic function and synaptic plasticity perhaps by generating reactive oxygen species resulting in spine loss (Selkoe 2002)....
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TL;DR: Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants, which provide a basis for NMDA channel heterogeneity in the brain.
3,419 citations
TL;DR: Recent evidence for structural forms of synaptic plasticity in the mammalian cortex involves cell type-specific structural plasticity: some boutons and dendritic spines appear and disappear, accompanied by synapse formation and elimination, respectively.
Abstract: Synaptic plasticity in adult neural circuits may involve the strengthening or weakening of existing synapses as well as structural plasticity, including synapse formation and elimination. Indeed, long-term in vivo imaging studies are beginning to reveal the structural dynamics of neocortical neurons in the normal and injured adult brain. Although the overall cell-specific morphology of axons and dendrites, as well as of a subpopulation of small synaptic structures, are remarkably stable, there is increasing evidence that experience-dependent plasticity of specific circuits in the somatosensory and visual cortex involves cell type-specific structural plasticity: some boutons and dendritic spines appear and disappear, accompanied by synapse formation and elimination, respectively. This Review focuses on recent evidence for such structural forms of synaptic plasticity in the mammalian cortex and outlines open questions.
1,696 citations
Additional excerpts
...In contrast, a smaller influx of calcium over a longer time course triggers the induction of long-term depression (LTD), which results in a decrease in synaptic efficiency via the removal of AMPARs from the postsynaptic membrane and the shrinkage of dendritic spines (Holtmaat and Svoboda 2009)....
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...In contrast, a smaller influx of calcium over a longer time course triggers the induction of long-term depression (LTD), which results in a decrease in synaptic efficiency via the removal of AMPARs from the postsynaptic membrane and the shrinkage of dendritic spines (Holtmaat and Svoboda 2009)....
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TL;DR: It is found that application of amyloid-β promoted endocytosis of NMDA receptors in cortical neurons, indicating a new mechanism by which amyloids-β can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
Abstract: Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
1,442 citations
TL;DR: Perturbations in the balance between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington's disease, and could be a common theme in the aetiology of neurodegenerative diseases.
Abstract: There is a long-standing paradox that NMDA (N-methyl-D-aspartate) receptors (NMDARs) can both promote neuronal health and kill neurons. Recent studies show that NMDAR-induced responses depend on the receptor location: stimulation of synaptic NMDARs, acting primarily through nuclear Ca(2+) signalling, leads to the build-up of a neuroprotective 'shield', whereas stimulation of extrasynaptic NMDARs promotes cell death. These differences result from the activation of distinct genomic programmes and from opposing actions on intracellular signalling pathways. Perturbations in the balance between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington's disease, and could be a common theme in the aetiology of neurodegenerative diseases. Neuroprotective therapies should aim to both enhance the effect of synaptic activity and disrupt extrasynaptic NMDAR-dependent death signalling.
1,373 citations
"Diversity in NMDA Receptor Composit..." refers background in this paper
...Whereas the activation of synaptic NMDARs triggers intracellular cascades promoting cell survival, the entry of calcium through extrasynaptic NMDARs leads to neuronal death via mitochondrial dysfunction (a process known as excitotoxicity) (Hardingham and Bading 2010)....
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