Showing papers on "NMDA receptor published in 2015"
TL;DR: Findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibodies-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.
Abstract: Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients’ antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients’ antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients’ or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients’ cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13–18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.
474 citations
TL;DR: In the greatest majority of the cell lines ionotropic glutamate receptors are present, co-existing to CySS/glutamate antiporters and metabotropic glutamate receptor, supporting the assumption that excitotoxicity effect in these cells is accumulative.
Abstract: Although glutamate is one of the most important excitatory neurotransmitters of the central nervous system, its excessive extracellular concentration leads to uncontrolled continuous depolarization of neurons, a toxic process called, excitotoxicity. In excitotoxicity glutamate triggers the rise of intracellular Ca2+ influx, followed by up regulation of nNOS, dysfunction of mitochondria, ROS production, ER stress and release of lysosomal enzymes. Excessive calcium concentration is the key mediator of glutamate toxicity through over activation of ionotropic and metabotropic receptors. In addition, glutamate accumulation can also inhibit cystine uptake by reversing the action of the cystine/glutamate antiporter. Reversal of the antiporter action reinforces the aforementioned events by depleting neurons of cysteine and eventually glutathione’s reducing potential. Various cell lines have been employed in the pursuit to understand the mechanism(s) by which excitotoxicity affects the cells leading them ultimately to their demise. In some cell lines glutamate toxicity is exerted mainly through over activation of NMDA, AMPA or Kainate receptors whereas in other cell lines lacking such receptors, the toxicity is due to glutamate induced oxidative stress. However in the greatest majority of the cell lines ionotropic-glutamate receptors are present, co-existing to cystine/glutamate antiporters and metabotropic glutamate receptors, supporting the assumption that excitotoxicity effect in these cells is accumulative. Different cell lines differ in their responses when exposed to glutamate. In this review article the responses of PC12, SH-SY5Y, HT-22, NT-2, OLCs, C6, primary rat cortical neurons, RGC-5 and SCN2.2 cell systems are systematically collected and analyzed.
311 citations
TL;DR: Postmortem studies of brain tissue from individuals affected by schizophrenia found consistent evidence of morphological alterations of dendrites of glutamatergic neurons in the cerebral cortex of subjects with schizophrenia and of reduced levels of the axon bouton marker synaptophysin.
Abstract: A number of studies have indicated that antagonists of the N-methyl-d-aspartate subtypes of glutamate receptors can cause schizophrenia-like symptoms in healthy individuals and exacerbate symptoms in individuals with schizophrenia. These findings have led to the glutamate hypothesis of schizophrenia. Here we review the evidence for this hypothesis in postmortem studies of brain tissue from individuals affected by schizophrenia, summarizing studies of glutamate neuron morphology, of expression of glutamate receptors and transporters, and of the synthesizing and metabolizing enzymes for glutamate and its co-agonists. We found consistent evidence of morphological alterations of dendrites of glutamatergic neurons in the cerebral cortex of subjects with schizophrenia and of reduced levels of the axon bouton marker synaptophysin. There were no consistent alterations of mRNA expression of glutamate receptors, although there has been limited study of the corresponding proteins. Studies of the glutamate metabolic pathway have been limited, although there is some evidence that excitatory amino acid transporter-2, glutamine synthetase, and glutaminase have altered expression in schizophrenia. Future studies would benefit from additional direct examination of glutamatergic proteins. Further advances, such as selective testing of synaptic microdomains, cortical layers, and neuronal subtypes, may also be required to elucidate the nature of glutamate signaling impairments in schizophrenia.
250 citations
TL;DR: It is concluded that NMDARs are not synonymous for either LTP or memory, as they mediate the induction of other forms of synaptic plasticity and are important for synaptic transmission.
238 citations
TL;DR: Subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as revealed by magnetoencephalographic recordings.
Abstract: Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine's effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n = 25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effects demonstrated their own set of temporal dynamics. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. Based on these results, we suggest that the antidepressant effects of ketamine may depend on its ability to change the balance of frontoparietal connectivity patterns.
SIGNIFICANCE STATEMENT In this paper, we found that subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as revealed by magnetoencephalographic recordings. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. The alterations in frontoparietal connectivity patterns we observe here may be important in generating the antidepressant response to ketamine.
234 citations
TL;DR: Targeting of these major sites of neuronal damage using pharmacological agents is discussed in terms of potential therapeutic approaches for neurological disorders.
Abstract: In stroke and neurodegenerative disease, neuronal excitotoxicity, caused by increased extracellular glutamate levels, is known to result in calcium overload and mitochondrial dysfunction. Mitochondrial deficits may involve a deficiency in energy supply as well as generation of high levels of oxidants which are key contributors to neuronal cell death through necrotic and apoptotic mechanisms. Excessive glutamate receptor stimulation also results in increased nitric oxide generation which can be detrimental to cells as nitric oxide interacts with superoxide to form the toxic molecule peroxynitrite. High level oxidant production elicits neuronal apoptosis through the actions of proapoptotic Bcl-2 family members resulting in mitochondrial permeability transition pore opening. In addition to apoptotic responses to severe stress, accumulation of misfolded proteins and high levels of oxidants can elicit endoplasmic reticulum (ER) stress pathways which may also contribute to induction of apoptosis. Two categories of therapeutics are discussed that impact major pro-death events that include induction of oxidants, calcium overload, and ER stress. The first category of therapeutic agent includes the amino acid taurine which prevents calcium overload and is also capable of preventing ER stress by inhibiting specific ER stress pathways. The second category involves N-methyl-D-aspartate receptor (NMDA receptor) partial antagonists illustrated by S-Methyl-N, N-diethyldithiocarbamate sulfoxide (DETC-MeSO), and memantine. DETC-MeSO is protective through preventing excitotoxicity and calcium overload and by blocking specific ER stress pathways. Another NMDA receptor partial antagonist is memantine which prevents excessive glutamate excitation but also remarkably allows maintenance of physiological neurotransmission. Targeting of these major sites of neuronal damage using pharmacological agents is discussed in terms of potential therapeutic approaches for neurological disorders.
233 citations
TL;DR: Findings from gene expression studies of a large cohort of postmortem subjects reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.
Abstract: Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.
230 citations
TL;DR: This review details the recent genetic and neurobiological findings that link N-methyl-D-aspartate receptor (NMDAR) hypofunction to the etiology of schizophrenia and highlights potential treatment strategies that augment NMDA receptor function to treat the synaptic deficits and cognitive impairments.
193 citations
TL;DR: DREADD-mediated glutamate gliotransmission inhibited cue-induced reinstatement of cocaine seeking by stimulating release-regulating group II metabotropic glutamate receptor autoreceptors to inhibit cue- induced synaptic glutamate spillover.
188 citations
TL;DR: The data indicate that the hippocampal CA2 is important for attacking in response to a male intruder and that the Avpr1b, likely through its role in regulating CA2 synaptic plasticity, is a necessary mediator.
Abstract: The vasopressin 1b receptor (Avpr1b) is critical for social memory and social aggression in rodents, yet little is known about its specific roles in these behaviors. Some clues to Avpr1b function can be gained from its profile of expression in the brain, which is largely limited to the pyramidal neurons of the CA2 region of the hippocampus, and from experiments showing that inactivation of the gene or antagonism of the receptor leads to a reduction in social aggression. Here we show that partial replacement of the Avpr1b through lentiviral delivery into the dorsal CA2 region restored the probability of socially motivated attack behavior in total Avpr1b knockout mice, without altering anxiety-like behaviors. To further explore the role of the Avpr1b in this hippocampal region, we examined the effects of Avpr1b agonists on pyramidal neurons in mouse and rat hippocampal slices. We found that selective Avpr1b agonists induced significant potentiation of excitatory synaptic responses in CA2, but not in CA1 or in slices from Avpr1b knockout mice. In a way that is mechanistically very similar to synaptic potentiation induced by oxytocin, Avpr1b agonist-induced potentiation of CA2 synapses relies on NMDA (N-methyl-D-aspartic acid) receptor activation, calcium and calcium/calmodulin-dependent protein kinase II activity, but not on cAMP-dependent protein kinase activity or presynaptic mechanisms. Our data indicate that the hippocampal CA2 is important for attacking in response to a male intruder and that the Avpr1b, likely through its role in regulating CA2 synaptic plasticity, is a necessary mediator.
187 citations
TL;DR: In vivo two-photon microscopy in the mouse somatosensory barrel cortex found that acute whisker stimulation led to a significant increase in the intensity of surface AMPAR GluA1 subunit (sGluA 1) in both spines and dendritic shafts and a small increase in spine size relative to prestimulation values.
Abstract: Regulation of AMPA receptor (AMPAR) membrane trafficking is critical for synaptic plasticity, as well as for learning and memory. However, the mechanisms of AMPAR trafficking in vivo remain elusive. Using in vivo two-photon microscopy in the mouse somatosensory barrel cortex, we found that acute whisker stimulation led to a significant increase in the intensity of surface AMPAR GluA1 subunit (sGluA1) in both spines and dendritic shafts and a small increase in spine size relative to prestimulation values. Interestingly, the initial spine properties biased spine changes following whisker stimulation. Changes in spine sGluA1 intensity were positively correlated with changes in spine size and dendritic shaft sGluA1 intensity following whisker stimulation. The increase in spine sGluA1 intensity evoked by whisker stimulation was NMDA receptor dependent and long lasting, similar to major forms of synaptic plasticity in the brain. In this study we were able to observe experience-dependent AMPAR trafficking in real time and characterize, in vivo, a major form of synaptic plasticity in the brain.
TL;DR: Compared with 7,8-DHF and ANA-12, ketamine is a longer-lasting antidepressant in the social defeat stress model, and synaptogenesis may be required for the mechanisms that promote sustained antidepressant effects of ketamine.
Abstract: Brain-derived neurotrophic factor (BDNF) and signaling at its receptor, tropomyosin-related kinase B (TrkB), are implicated in the rapid and long-lasting antidepressant effects of ketamine Moreover, a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), and/or TrkB antagonist, ANA-12, shows antidepressant effects in animal models of depression The objective of this study is to compare the influence of ketamine, 7,8-DHF, and ANA-12 on antidepressant activity in the social defeat stress model In the tail suspension and forced swimming tests, ketamine, 7,8-DHF, or ANA-12 markedly attenuated the increased immobility time in depressed mice compared with the vehicle-treated group In the sucrose preference test, all drugs significantly improved the reduced preference in depressed mice at both 1 and 3 days after a single dose Antidepressant effect of ketamine, but not 7,8-DHF or ANA-12, was still detectable 7 days after a single dose Western blot analyses showed that ketamine, but not 7,8-DHF or ANA-12, markedly attenuated reduced levels of BDNF and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex (PFC), dentate gyrus (DG), and CA3 of the hippocampus in depressed mice 8 days after a single dose Furthermore, ketamine markedly increased reduced levels of GluA1 in the PFC and DG of depressed mice In contrast, ketamine showed no effect against increased levels of BDNF, PSD-95, and GluA1 observed in the nucleus accumbens of depressed mice Compared with 7,8-DHF and ANA-12, ketamine is a longer-lasting antidepressant in the social defeat stress model, and synaptogenesis may be required for the mechanisms that promote sustained antidepressant effects of ketamine
TL;DR: Treatment of IRSp53−/− mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist, normalized social interaction and suggested that deviation of NMDar function in either direction leads to social deficits and that correcting the deviation has beneficial effects.
Abstract: Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53(-/-) mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects.
TL;DR: Delays-dependent effect of AP5 in the HPC-PRH on object-in-place memory, accords with its effects in the PRH, on single item object recognition memory, thereby suggesting that a single PRH synaptic plasticity mechanism underpins different recognition memory processes.
Abstract: Object-in-place associative recognition memory depends on an interaction between the hippocampus (HPC), perirhinal (PRH), and medial prefrontal (mPFC) cortices, yet the contribution of glutamate receptor neurotransmission to these interactions is unknown. NMDA receptors (NMDAR) in the HPC were critical for encoding of object-in-place memory but not for single-item object recognition. Next, a disconnection procedure was used to examine the importance of “concurrent” glutamate neurotransmission in the HPC-mPFC and HPC-PRH. Contralateral unilateral infusions of NBQX (AMPAR antagonist), into the HPC-mPFC, or HPC-PRH, either before acquisition or test, impaired object-in-place performance. Thus, both circuits are necessary for encoding and retrieval. Crossed unilateral AP5 (NMDAR antagonist) infusions into the HPC-mPFC or HPC-PRH impaired encoding, but not retrieval. Specifically crossed HPC-mPFC infusions impaired both short-term (5 min) and longer term (1 h) memory while HPC-PRH infusions impaired longer term memory only. This delay-dependent effect of AP5 in the HPC-PRH on object-in-place memory, accords with its effects in the PRH, on single item object recognition memory, thereby suggesting that a single PRH synaptic plasticity mechanism underpins different recognition memory processes. Further, blocking excitatory neurotransmission in any pair of structures within the networks impaired “both” encoding and retrieval, thus object-in-place memory clearly requires network interdependency across multiple structures.
TL;DR: It is suggested that NR1 and Akt/mTOR signaling are important therapeutic targets for depression.
Abstract: Yueju, a Traditional Chinese Medicine formula, exhibited fast-onset antidepressant responses similar to ketamine. This study focused on assessing the rapid and persistent antidepressant efficacy of Yueju and ketamine in chronically stressed mice and its association with alternations in prefrontal N-methyl-D-aspartate (NMDA) receptor and mammalian target of rapamycin (mTOR)-related activity. Chronic mild stress (CMS) led to deficits in sucrose preference test (SPT), forced swim test, tail suspension test, and novelty-suppressed feeding test, which were improved differently by acute Yueju or ketamine administration. The improvement in SPT started as soon as 2 hours post Yueju and ketamine but lasted for 6 days only by Yueju. Body weight was regained by Yueju more than ketamine at post-drug administration day (PAD) 6. CMS decreased phosphorylation of the mTOR effectors 4E-BP1 and p70S6K, their upstream regulators ERK and Akt, and downstream targets including synaptic protein GluR1. Yueju or ketamine reversed these changes at PAD 2, but only Yueju reversed phosphor-Akt at PAD 6. CMS selectively and lastingly increased NMDA receptor subunit NR1 expression, which was reversed by ketamine or Yueju at PAD 2 but only by Yueju at PAD 6. These findings suggest that NR1 and Akt/mTOR signaling are important therapeutic targets for depression.
TL;DR: It is suggested that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors in iKO mice.
TL;DR: The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors may disturb the normal migration pattern when present during early corticogenesis.
Abstract: Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca2+ transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e. neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g. anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis.
TL;DR: The results support a model in which NMDAR signaling, independent of ion flux, drives structural shrinkage at spiny synapses, and provide fundamental new insights into the signaling mechanisms that support experience-dependent changes in brain structure.
Abstract: The elimination of dendritic spine synapses is a critical step in the refinement of neuronal circuits during development of the cerebral cortex. Several studies have shown that activity-induced shrinkage and retraction of dendritic spines depend on activation of the NMDA-type glutamate receptor (NMDAR), which leads to influx of extracellular calcium ions and activation of calcium-dependent phosphatases that modify regulators of the spine cytoskeleton, suggesting that influx of extracellular calcium ions drives spine shrinkage. Intriguingly, a recent report revealed a novel non-ionotropic function of the NMDAR in the regulation of synaptic strength, which relies on glutamate binding but is independent of ion flux through the receptor (Nabavi et al., 2013). Here, we tested whether non-ionotropic NMDAR signaling could also play a role in driving structural plasticity of dendritic spines. Using two-photon glutamate uncaging and time-lapse imaging of rat hippocampal CA1 neurons, we show that low-frequency glutamatergic stimulation results in shrinkage of dendritic spines even in the presence of the NMDAR d-serine/glycine binding site antagonist 7-chlorokynurenic acid (7CK), which fully blocks NMDAR-mediated currents and Ca2+ transients. Notably, application of 7CK or MK-801 also converts spine enlargement resulting from a high-frequency uncaging stimulus into spine shrinkage, demonstrating that strong Ca2+ influx through the NMDAR normally overcomes a non-ionotropic shrinkage signal to drive spine growth. Our results support a model in which NMDAR signaling, independent of ion flux, drives structural shrinkage at spiny synapses.
SIGNIFICANCE STATEMENT Dendritic spine elimination is vital for the refinement of neural circuits during development and has been linked to improvements in behavioral performance in the adult. Spine shrinkage and elimination have been widely accepted to depend on Ca2+ influx through NMDA-type glutamate receptors (NMDARs) in conjunction with long-term depression (LTD) of synaptic strength. Here, we use two-photon glutamate uncaging and time-lapse imaging to show that non-ionotropic NMDAR signaling can drive shrinkage of dendritic spines, independent of NMDAR-mediated Ca2+ influx. Signaling through p38 MAPK was required for this activity-dependent spine shrinkage. Our results provide fundamental new insights into the signaling mechanisms that support experience-dependent changes in brain structure.
TL;DR: Mechanisms of epigenetic plasticity in the hippocampus are elucidated in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors, revealing a window of epigenetics plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.
Abstract: Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up- and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.
TL;DR: An unprecedented relationship in the identity of the coagonist not only with the GluN2 subunit composition at synaptic NMDARs but also with astrocyte activity in the developing and mature hippocampus that reconciles the complementary functions of d-serine and glycine in modulating N MDARs during the maturation of tripartite glutamatergic synapses is disclosed.
Abstract: NMDA receptors (NMDARs) require the coagonists D-serine or glycine for their activation, but whether the identity of the coagonist could be synapse specific and developmentally regulated remains elusive. We therefore investigated the contribution of D-serine and glycine by recording NMDAR-mediated responses at hippocampal Schaffer collaterals (SC)-CA1 and medial perforant path-dentate gyrus (mPP-DG) synapses in juvenile and adult rats. Selective depletion of endogenous coagonists with enzymatic scavengers as well as pharmacological inhibition of endogenous D-amino acid oxidase activity revealed that D-serine is the preferred coagonist at SC-CA1 mature synapses, whereas, unexpectedly, glycine is mainly involved at mPP-DG synapses. Nevertheless, both coagonist functions are driven by the levels of synaptic activity as inferred by recording long-term potentiation generated at both connections. This regional compartmentalization in the coagonist identity is associated to different GluN1/GluN2A to GluN1/GluN2B subunit composition of synaptic NMDARs. During postnatal development, the replacement of GluN2B- by GluN2A-containing NMDARs at SC-CA1 synapses parallels a change in the identity of the coagonist from glycine to D-serine. In contrast, NMDARs subunit composition at mPP-DG synapses is not altered and glycine remains the main coagonist throughout postnatal development. Altogether, our observations disclose an unprecedented relationship in the identity of the coagonist not only with the GluN2 subunit composition at synaptic NMDARs but also with astrocyte activity in the developing and mature hippocampus that reconciles the complementary functions of D-serine And Glycine In Modulating Nmdars During The Maturation Of Tripartite Glutamatergic Synapses.
TL;DR: Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models and suggest that modulation of NMDAR currents is not critical for in-vivo efficacy, providing surprising new mechanistic insights into the actions of mGlu5 PAMs.
TL;DR: An overview of the research findings regarding changes in expression of variousNMDA receptor subunits and deficits in NMDA receptor function during senescence and its implication in age-associated impaired hippocampal-dependent memory function is presented.
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.
TL;DR: In contrast to transcranial direct current stimulation (tDCS), aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tR NS depend upon different mechanisms.
Abstract: Background: Application of transcranial random noise stimulation (tRNS) between 0.1 and 640 Hz of the primary motor cortex (M1) for 10 minutes induces a persistent excitability increase lasting for at least 60 minutes. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1mA for 10mins stimulation duration and a pharmacological agent (or sham) on 8 healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency towards inhibiting MEPs 5-60 mins poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS. Conclusions: In contrast to transcranial direct current stimulation (tDCS), aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.
TL;DR: It is reported here that synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder.
TL;DR: The result of these processes is neuronal necrosis, which is a programmed cell death that is the basis of all acute neuronal injury in the adult brain.
Abstract: Excitotoxicity involves the excessive release of glutamate from presynaptic nerve terminals and from reversal of astrocytic glutamate uptake, when there is excessive neuronal depolarization. N-methyl-d-aspartate (NMDA) receptors, a subtype of glutamate receptor, are activated in postsynaptic neurons, opening their receptor-operated cation channels to allow Ca2 + influx. The Ca2 + influx activates two enzymes, calpain I and neuronal nitric oxide synthase (nNOS). Calpain I activation produces mitochondrial release of cytochrome c (cyt c), truncated apoptosis-inducing factor (tAIF) and endonuclease G (endoG), the lysosomal release of cathepsins B and D and DNase II, and inactivation of the plasma membrane Na+–Ca2 + exchanger, which add to the buildup of intracellular Ca2 +. tAIF is involved in large-scale DNA cleavage and cyt c may be involved in chromatin condensation; endoG produces internucleosomal DNA cleavage. The nuclear actions of the other proteins have not been determined. nNOS forms nitric oxide (NO), which reacts with superoxide (O2−) to form peroxynitrite (ONOO−). These free radicals damage cellular membranes, intracellular proteins and DNA. DNA damage activates poly(ADP-ribose) polymerase-1 (PARP-1), which produces poly(ADP-ribose) (PAR) polymers that exit nuclei and translocate to mitochondrial membranes, also releasing AIF. Poly(ADP-ribose) glycohydrolase hydrolyzes PAR polymers into ADP-ribose molecules, which translocate to plasma membranes, activating melastatin-like transient receptor potential 2 (TRPM-2) channels, which open, allowing Ca2 + influx into neurons. NADPH oxidase (NOX1) transfers electrons across cellular membranes, producing O2−. The result of these processes is neuronal necrosis, which is a programmed cell death that is the basis of all acute neuronal injury in the adult brain.
TL;DR: The ability of ketamine to exert a rapid effect provides a unique opportunity to elucidate the types of acute synaptic plasticity changes that can be recruited to counter depression symptoms.
TL;DR: This study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions, and suggests that the development of TAar1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions.
TL;DR: This study demonstrates that transmembrane information transfer through the NMDAR is possible in the absence of ion flow through the receptor, and indicates that extracellular ligand binding to the N MDAR can transmit conformational information into the cell in the presence of ions.
Abstract: The NMDA receptor (R) plays important roles in brain physiology and pathology as an ion channel. Here we examine the ion flow-independent coupling of agonist to the NMDAR cytoplasmic domain (cd). We measure FRET between fluorescently tagged cytoplasmic domains of GluN1 subunits of NMDARs expressed in neurons. Different neuronal compartments display varying levels of FRET, consistent with different NMDARcd conformations. Agonist binding drives a rapid and transient ion flow-independent reduction in FRET between GluN1 subunits within individual NMDARs. Intracellular infusion of an antibody targeting the GluN1 cytoplasmic domain blocks agonist-driven FRET changes in the absence of ion flow, supporting agonist-driven movement of the NMDARcd. These studies indicate that extracellular ligand binding to the NMDAR can transmit conformational information into the cell in the absence of ion flow.
TL;DR: Case reports suggest that sigma-1 receptor agonists, including fluvoxamine, and ifenprodil, may be effective in the treatment of cognitive impairment in schizophrenia, delirium in elderly people, and flashbacks in post-traumatic stress disorder.
1 Jan 2015
TL;DR: In this paper, the effect of the NMDAR antagonist D-2-amino-5-phosphopentanoic acid (APV) and the NMDA receptor subunit type 2B (NR2B)-selective antagonist ifenprodil on the threshold, peak amplitude, and area of evoked epileptiform discharges in brain slices from lesioned animals.
Abstract: Recent studies have demonstrated an important role for the N-methyl-D-aspartate receptor (NMDAR) in epilepsy. NMDARs have also been shown to play a critical role in hyperexcitability associated with several animal models of human epilepsy. Using whole-cell voltage clamp recordings in brain slices, we studied evoked paroxysmal discharges in the freeze-lesion model of neocortical microgyria. The voltage dependence of epileptiform discharges indicated that these paroxysmal events were produced by a complex pattern of excitatory and inhibitory inputs. We examined the effect of the NMDAR antagonist D-2-amino-5-phosphopentanoic acid (APV) and the NMDA receptor subunit type 2B (NR2B)-selective antagonist ifenprodil on the threshold, peak amplitude, and area of evoked epileptiform discharges in brain slices from lesioned animals. Both compounds consistently raised the threshold for evoking the discharge but had modest effects on the discharge peak and amplitude. For comparison with nonlesioned cortex, we examined the effects of ifenprodil on the epileptiform discharge evoked in the presence of 2 microM bicuculline (partial disinhibition). In slices from nonlesioned cortex, 10 microM ifenprodil had little effect on the threshold whereas 71% of the recordings in bicuculline-treated lesioned cortex showed a >25% increase in threshold. These results suggest that NR2B-containing receptors are functionally enhanced in freeze-lesioned cortex and may contribute to the abnormal hyperexcitability observed in this model of neocortical microgyria.