Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-methyl-d-aspartate receptors (NMDARs) play a critical role in transducing neuronal activity patterns into changes in synaptic strength. However, how they mediate this transduction in response to physiological stimuli has remained elusive. In particular, it has been debated whether different NMDAR subtypes play opposing signaling roles in synaptic plasticity. Using perforated patch-clamp recordings from pairs of synaptically connected glutamatergic neurons in dissociated hippocampal culture, we found that spike-timing-dependent potentiation induced by pairing pre- and postsynaptic spikes required the activation of a fast component of NMDAR current that is likely to be mediated by NR2A-containing NMDARs (NR2A-NRs). In contrast, spike-timing-dependent depression required a slow component of NMDAR current carried by NR2B-containing NMDARs (NR2B-NRs). CV analysis showed that the locus of this depression was primarily presynaptic in pairs of cells making strong synaptic connections, whereas weaker synapses showed no clear preference for pre- or postsynaptic expression. This depression was not significantly reduced by antagonism of the CB1 receptor, in contrast to spike-timing-dependent depression in the neocortex that requires presynaptic CB1 signaling. With blockade of NR2B-NRs, spike triplets that contained both potentiating and depressing spike-timing components induced net potentiation. However, when the putative NR2A-NR population is inhibited, these spike triplets resulted in either depression or no net change, depending on the temporal order of the spike-timing components. These results imply a dynamic competition between signaling modules that can be biased by differentially antagonizing NMDAR subtypes during the induction of spike-timing-dependent plasticity. Using a simple model, we show that such a modular competition recapitulates our observations.
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PMID:Modular competition driven by NMDA receptor subtypes in spike-timing-dependent plasticity. 1726 56

Light deprivation lowers the threshold for long-term depression (LTD) and long-term potentiation (LTP) in visual cortex by a process termed metaplasticity, but the mechanism is unknown. The decreased LTD/P threshold correlates with a decrease in the ratio of NR2A to NR2B subunits of cortical NMDA receptors (NMDARs) and a slowing of NMDAR-mediated excitatory postsynaptic currents (EPSCs). However, whether and how changes in NR2 subunit expression contribute to LTD and LTP have been controversial. In the present study, we used an NR2A knockout (KO) mouse to examine the role of this subunit in the experience-dependent modulation of NMDAR properties, LTD, and LTP. We found that deletion of NR2A abrogates the effects of visual experience on NMDAR EPSCs and prevents metaplasticity of LTP and LTD. These data support the hypothesis that experience-dependent changes in NR2A/B are functionally significant and yield a mechanism for an adjustable synaptic modification threshold in visual cortex.
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PMID:Obligatory role of NR2A for metaplasticity in visual cortex. 1729 52

Chronic nicotine treatment reverses hypothyroidism-induced impairment of hippocampus-dependent spatial memory and long-term potentiation (LTP). We investigated the effect of hypothyroidism on long-term depression (LTD) and possible protection by nicotine. Following paired pulse stimulation, LTD was expressed in hippocampal area CA1 of anesthetized thyroidectomized, euthyroid (sham control), nicotine-treated and nicotine-treated thyroidectomized (hypothyroid) rats. In hypothyroid rats, a significantly higher LTD magnitude was seen compared with that in control rats. A brief train of stimuli (5 pulses at 100 Hz), which did not affect synaptic transmission in control rats, induced a robust LTD in hypothyroid rats suggesting facilitation of LTD expression in these rats. Chronic nicotine treatment (1 mg/kg, 2x day) of hypothyroid rats reversed hypothyroidism-induced enhancement and facilitation of LTD. Western blot analysis of the NMDA receptor subunits in the membranous fractions of hippocampal area CA1 neurons revealed that hypothyroidism reduced NR1 and increased NR2B without affecting NR2A protein levels. These changes in NMDA receptors in hypothyroid rats were reversed by chronic nicotine treatment. Hypothyroidism did not alter BDNF or nicotinic acetylcholine receptor (nAChR) levels. However, nicotine treatment increased protein levels of these molecules in both euthyroid and hypothyroid rats. Our results suggest that alterations in the levels of NMDA receptor subunits may account for the facilitation and enhancement of LTD in hypothyroidism.
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PMID:Adult-onset hypothyroidism facilitates and enhances LTD: reversal by chronic nicotine treatment. 1733 37

Exposure to an enriched environment (EE) has been shown to induce cortical plasticity. Considerable amount of research is focused on the effects of EE in the hippocampus; however, effects of EE on other brain regions and the mechanisms involved are not well known. To investigate this, we induced cortical plasticity by placing mice in an EE for one month and measured the effects of EE in the anterior cingulate cortex (ACC). Here, we show that EE enhanced the expression of the plasticity gene, egr-1, in the ACC of EE animals accompanied by enhanced cingulate long-term potentiation (LTP) and decreased cingulate long-term depression (LTD). The increased NMDA receptor NR2B/NR2A subunits current ratio is associated with the plasticity seen in the ACC while total protein levels remain unchanged. Furthermore, behavioral experiments show that these mice exposed to EE demonstrate enhanced responses to acute and long-term inflammation. Our findings suggest that exposure to EE alters physiological properties within the ACC which results in enhanced responses to inflammation.
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PMID:Alteration of cingulate long-term plasticity and behavioral sensitization to inflammation by environmental enrichment. 1752 19

In the present study, we aimed to investigate the role of N-methyl-D-aspartate (NMDA) receptors in the antidepressant-like effects of a sigma(1) receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA-4503), in the olfactory bulbectomized (OB) rat model of depression. A symptomatology-based behavioral investigation was made by reconstructing in OB rats the symptoms of depression, such as psychomotor agitation, loss of interest, and cognitive dysfunction, using a typical antidepressant, desipramine, as a positive control. Repeated treatment with SA-4503 ameliorated the behavioral deficits in OB rats resembling depression symptoms in the open-field test, sexual behavior test, and cued and contextual fear-conditioning test. SA-4503 displayed advantages over desipramine in the sexual behavior test. SA-4503 also reversed the decrease in the protein expression of NMDA receptor subunit (NR)1, but not NR2A or NR2B, in the prefrontal cortex, hippocampus, and amygdala of OB rats. The behavioral and neurochemical effects of SA-4503 were blocked by combined treatment with a specific sigma(1) receptor antagonist, N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride (NE-100). Furthermore, the effects of SA-4503 on the performance of OB rats in the behavioral tests were abrogated by acute treatment with an NMDA receptor antagonist, (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801). The present study indicated for the first time that the sigma(1) receptor agonist SA-4503 may have effects on depressive symptoms such as agitation, loss of interest, and impaired cognition, which are mediated by NMDA receptors.
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PMID:Role of N-methyl-D-aspartate receptors in antidepressant-like effects of sigma 1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA-4503) in olfactory bulbectomized rats. 1755 37

The direction of plasticity at CA3-CA1 hippocampal synapses is determined by the strength of afferent stimulation. Weak stimuli lead to long-term depression (LTD) and strong stimuli to long-term potentiation (LTP), but both require activation of synaptic N-methyl-D-aspartate receptors (NMDARs). These receptors are therefore necessary and required for the induction of plasticity at CA3-CA1 synapses even though they carry little of the current responsible for the basal excitatory post-synaptic potential (EPSP). The influx of Ca(2+) via NMDARs triggers the subsequent and persistent changes in the expression of alpha-amino-3-hydroxy-5 methylisoxazole-4-proprionic acid receptors (AMPARs) and these receptors are responsible for the major part of the basal EPSP. The degree of activity of NMDARs is determined in part by extracellular Mg(2+) and by the co-agonists for this receptor, glycine and D-serine. During strong stimulation, a relief of the voltage-dependent block of NMDARs by Mg(2+) provides a positive feedback for NMDAR Ca(2+) influx into postsynaptic CA1 spines. In this review, we discuss how the induction of LTP at CA3-CA1 synapses requires further signal amplification of NMDAR activity. We discuss how the regulation of NMDARs by protein kinases and phosphatases is brought into play. Evidence is presented that Src family kinases (SFKs) play a "core" role in the induction of LTP by enhancing the function and expression of NMDARs. At CA3-CA1 synapses, NMDARs are largely composed of NR1 (NMDA receptor subunit 1)-NR2A or NR1-NR2B containing subunits. Recent, but controversial, evidence has correlated NR1-NR2A receptors with the induction of LTP and NR1-NR2B receptors with LTD. However, LTP can be induced by activation of either subtype of NMDAR and the ratio of NR2A:NR2B receptors has been proposed as an alternative determinant of the direction of synaptic plasticity. Many transmitters and signal pathways can modify NMDAR function and expression and, for a given stimulus strength, they can potentially lead to a change in the balance between LTP and LTD. As opposed to the "core" mechanisms of LTP and LTD, the resulting alterations in this balance underlie "meta-plasticity." Thus, in addition to their contribution to core mechanisms, we will also discuss how Src-family kinases could preferentially target NR1-NR2A or NR1-NR2B receptors to alter the relative contribution of these receptor subtypes to synaptic plasticity.
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PMID:Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors. 1772 10

We examined synaptic plasticity in the dentate gyrus (DG) of the hippocampus in vitro in juvenile C57Bl6 mice (28-40 days of age), housed in control conditions with minimal enrichment (Controls) or with access to an exercise wheel (Runners). LTP expression was significantly greater in slices from Runners than in those from Controls, but could be blocked by APV in both groups. LTP was significantly reduced by NR2B subunit antagonists in both groups. NVP-AAM077, an antagonist with a higher preference for NR2A subunits over NR2B subunits, blocked LTP in slices from Runners and produced a slight depression in Control animals. LTD in the DG was also blocked by APV, but not by either of the NR2B specific antagonists. Strikingly, NVP-AAM077 prevented LTD in Runners, but not in Control animals, suggesting an increased involvement of NR2A subunits in LTD in animals that exercise. NVP-AAM077 did not block LTD in NR2A Knock Out (KO) animals that exercised, as expected. In an attempt to discern whether NMDA receptors located at extrasynaptic sites could play a role in the induction of LTD, DL-TBOA was used to block excitatory amino acid transport and increase extracellular glutamate levels. Under these conditions, LTD was not blocked by the co-application of a specific NR2B subunit antagonist in either group, but NVP-AAM077 again blocked LTD selectively in Runners. These results indicate that NR2A and NR2B subunits play a significant role in LTP in the DG, and that exercise can significantly alter the contribution of NMDA NR2A subunits to LTD.
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PMID:Effects of exercise on NMDA receptor subunit contributions to bidirectional synaptic plasticity in the mouse dentate gyrus. 1787 76

Whether the subunit composition of NMDA receptors (NMDARs) controls the direction of long-term plasticity is currently disputed. In the visual layers of NR2A-/- juvenile superior colliculus (SC), synapses lose miniature NMDAR currents, leaving NR2B-rich receptors in extrasynaptic regions. Compared with wild type (WT), evoked NMDAR currents in mutant neurons have slower rise and decay times and lower NMDAR/AMPAR current ratios. Moreover, NMDAR and L-type Ca2+ channel-dependent SC long-term potentiation (LTP) is absent in NR2A-/- cells, whereas both WT and mutant neurons show long-duration, low-frequency-induced, long-term depression (LLF-LTD) that is blocked by either AP-5, nimodipine, or Ro 25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol]. Thus, NMDAR currents or signaling localized at the postsynaptic density are essential to SC NMDAR-dependent LTP, whereas extrasynaptic or NR2B-rich NMDARs are necessary for LLF-LTD. However, synaptic NMDARs as well as the NR2A subunit are missing in NR2A-/- mice. Therefore, NR2 subunit-specific ligand binding/channel properties and/or separate signaling pathways interacting with NMDARs at synaptic versus extrasynaptic receptors could underlie these results.
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PMID:NR2A-/- mice lack long-term potentiation but retain NMDA receptor and L-type Ca2+ channel-dependent long-term depression in the juvenile superior colliculus. 1807 76

Activation of NMDA receptors (NMDARs) is highly involved in the potentiation and depression of synaptic transmission. NMDARs comprise NR1 and NR2B subunits in the neonatal forebrain, while the expression of NR2A subunit is increased over time, leading to shortening of NMDAR-mediated synaptic currents. It has been suggested that the developmental switch in the NMDAR subunit composition regulates synaptic plasticity, but its physiological role remains unclear. In this study, we examine the effects of the NMDAR subunit switch on the spike-timing-dependent plasticity and the synaptic weight dynamics and demonstrate that the subunit switch contributes to inducing two consecutive processes-the potentiation of weak synapses and the induction of the competition between them-at an adequately rapid rate. Regulation of NMDAR subunit expression can be considered as a mechanism that promotes rapid and stable growth of immature synapses.
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PMID:A model for synaptic development regulated by NMDA receptor subunit expression. 1820 21

The NMDA-type glutamate receptor is a heteromeric complex composed of the NR1 and at least one of the NR2 subunits. Switching from the NR2B to the NR2A subunit is thought to underlie functional alteration of the NMDA receptor during synaptic maturation, and it is generally believed that it results in preferential localization of NR2A subunits on the synaptic site and that of NR2B subunits on the extracellular site in the mature brain. It has also been proposed that activation of the NR2A and NR2B subunits results in long-term potentiation (LTP) and long-term depression (LTD), respectively. Furthermore, recent reports suggest that synaptic and extrasynaptic receptors may have distinct roles in synaptic plasticity as well as in gene expression associated with neuronal death. Here, we have investigated whether NR2B subunit-containing receptors are present and functional at mature synapses in the lateral nucleus of the amygdala (LA) and the CA1 region of the hippocampus, comparing their properties between the two brain regions. We have found, in contrast to the above hypotheses, that the NR2B subunit significantly contributes to synaptic transmission as well as LTP induction. Furthermore, its contribution is greater in the LA than in the CA1 region, and biophysical properties of NMDA receptors and the NR2B/NR2A ratio are different between the two brain regions. These results indicate that NR2B subunit-containing NMDA receptors accumulate on the synaptic site and are responsible for the unique properties of synaptic function and plasticity in the amygdala.
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PMID:Functional contributions of synaptically localized NR2B subunits of the NMDA receptor to synaptic transmission and long-term potentiation in the adult mouse CNS. 1837 11


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