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)

Zinc has complex effects on NMDA receptors (NMDARs) and may be an endogenous modulator of synaptic plasticity. In the CA1 region of rat hippocampal slices, we observed that low micromolar concentrations of zinc depress NMDAR synaptic responses by 40-50% and inhibit long-term depression (LTD) but not long-term potentiation (LTP). A combination of zinc plus ifenprodil, an inhibitor of NR1/NR2B receptors, produced no greater inhibition of synaptic NMDARs than either agent alone, suggesting overlapping effects on NMDARs. Similar to low micromolar zinc, ifenprodil inhibited LTD but not LTP. In contrast, low concentrations of 2-amino-5-phosphonovalerate (APV) did not block either LTP or LTD despite producing >50% inhibition of synaptic NMDARs. NVP-AAM077 ([(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl)-methyl]phosphonic acid), an antagonist with relative NR1/NR2A selectivity at low concentrations, also inhibited synaptic NMDARs by approximately 50% at 0.05 mum but failed to completely block either LTP or LTD. These results suggest that LTD induction depends on specific NMDARs with sensitivity to low micromolar zinc and ifenprodil, but LTP is less dependent on specific NMDAR subtypes. Because high-affinity sites of NR2A are likely occupied by ambient zinc, we also examined effects of extracellular zinc chelators. Zinc chelation blocked LTP but had no effect on LTD. This LTP inhibition was overcome by APV and NVP-AAM077 but not ifenprodil, suggesting that zinc chelation unmasks tonic NR1/NR2A activation that negatively modulates LTP.
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PMID:Zinc modulates bidirectional hippocampal plasticity by effects on NMDA receptors. 1682 75

The triggering of both NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus requires a rise in postsynaptic calcium. A prominent hypothesis has been that the detailed properties of this postsynaptic calcium signal dictate whether LTP or LTD is generated by a given pattern of synaptic activity. Recently, however, evidence has been presented that the subunit composition of the NMDA receptor (NMDAR) determines whether a synapse undergoes LTP or LTD with NR2A-containing NMDARs triggering LTP and NR2B-containing NMDARs triggering LTD. In the present study, the role of NR2B-containing synaptic NMDARs in the induction of LTD in CA1 pyramidal cells has been studied using the selective NR2B antagonists, ifenprodil and Ro25-6981. While both antagonists reduced NMDAR-mediated synaptic currents, neither prevented induction of LTD. These results demonstrate that activation of NR2B-containing NMDARs is not an absolute requirement for the induction of LTD in the hippocampus.
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PMID:Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression. 1689 58

The role of NMDA receptors in the induction of long-term potentiation (LTP) and long-term depression (LTD) is well established but which particular NR2 subunits are involved in these plasticity processes is still a matter of controversy. We have studied the effects of subtype selective NMDA receptor antagonists on LTP induced by high frequency stimulation (100 Hz for 1s) and LTD induced by low frequency stimulation (1 Hz for 15 min) in the CA1 region of hippocampal slices from 14 day old Wistar rats. Against recombinant receptors in HEK293 cells NVP-AAM077 (NVP) was approximately 14-fold selective for NR2A vs NR2B receptors, whilst Ro 25-6981 (Ro) was highly selective for NR2B receptors. On NMDA receptor-mediated EPSCs from Schaffer collaterals in CA1 neurones, NVP and Ro both reduced the amplitude but differentially affected the time constant of decay. The data are compatible with the selective effect of NVP (0.1 microM) and Ro (4 microM) on native NR2A and NBR2B receptors, respectively. NVP reduced both LTP and LTD whereas Ro reduced only LTP. Thus, LTP was reduced by 63% at 0.1 microM NVP and almost completely at 0.4 microM whereas 5 microM Ro reduced LTP by 45%. These data are consistent with a role for both NR2A and NR2B in the induction of LTP, under our experimental conditions. In comparison, LTD was unaffected by Ro (5 microM) even in the presence of a glutamate uptake inhibitor threo-beta-benzylaspartic acid (TBOA) to increase the concentration of glutamate at NR2B containing receptors. NVP (0.2-0.4 microM), however, produced a concentration dependent inhibition of LTD which was complete at 0.4 microM. The lack of effect of 0.1 microM NVP on LTD contrasts with its marked effect on LTP and raises the possibility that different NVP-sensitive NR2 subunit-containing NMDA receptors are required for LTP and LTD in this preparation.
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PMID:Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. 1690 7

Behavioral stress facilitates long-term depression but impairs long-term potentiation in the hippocampus. Recent evidence in vitro demonstrates that the NR2B-containing N-methyl-D-aspartate subtype glutamate receptor antagonist Ro25-6981 prevents the behavioral stress-facilitated hippocampal long-term depression. It is, however, unknown whether Ro25-6981 influences hippocampal long-term depression and long-term potentiation induction in vivo under stressful condition. Here, we found that infusion of Ro25-6981 (2.3 microg in 6 microl, intracerebroventricular for 10 min) 30 min before low-frequency stimulation prevented the facilitation of hippocampal long-term depression by acute stress in anesthetized adult rats. Moreover, infusion of Ro25-6981 30 min before high-frequency stimulation reversed stress-impaired hippocampal long-term potentiation. These results suggest that the NR2B-containing N-methyl-D-aspartate subtype glutamate receptors are crucial for the effects of behavioral stress on hippocampal long-term depression and long-term potentiation in vivo.
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PMID:NR2B-containing N-methyl-D-aspartate subtype glutamate receptors regulate the acute stress effect on hippocampal long-term potentiation/long-term depression in vivo. 1695 82

It has recently been proposed that activation of the NR2A subunit results in Long-term potentiation (LTP) induction, whereas activation of the NR2B subunit results in long-term depression (LTD) induction. The present study undertakes to replicate these findings in vivo to determine if a role for specific subunits in synaptic plasticity can be shown in the intact brain. Field recordings were made from the CA1 subfield of the hippocampus using Schaffer collateral stimulation in anesthetized male Sprague-Dawley rats. Antagonists of the N-methyl-D-aspartate receptors NR2A and NR2B subunits were administered by either intraperitoneal (i.p.) or intrahippocampal (i.h.) injections to assess their involvement in LTP (100 Hz stimuli) and LTD (200 Paired-burst stimuli). i.h. injection of Ro25-6981 (100 microM) significantly attenuated hippocampal LTP expression and completely blocked LTD expression. When administered i.p., Ro25-6981 (6 mg/kg) again blocked LTD, but did not significantly diminish the expression of LTP. When NVP-AAM077 was administered i.h. (80 microM) both LTP and LTD were completely abolished. The administration of this compound i.p. (1.2 mg/kg) also significantly attenuated LTP, but did not affect LTD. These data suggest that both NR2A and NR2B subunits can play roles in LTP and LTD in the hippocampus in vivo.
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PMID:Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo. 1702 79

Insufficient sleep impairs cognitive functions in humans and animals. However, whether long-term synaptic plasticity, a cellular substrate of learning and memory, is compromised by sleep loss per se remains unclear because of confounding factors related to sleep deprivation (SD) procedures in rodents. Using an ex vivo approach in C57BL/6J mice, we show that sleep loss rapidly and reversibly alters bidirectional synaptic plasticity in the CA1 area of the hippocampus. A brief (approximately 4 h) total SD, respecting the temporal parameters of sleep regulation and maintaining unaltered low corticosterone levels, shifted the modification threshold for long-term depression/long-term potentiation (LTP) along the stimulation frequency axis (1-100 Hz) toward the right. Reducing exposure to sensory stimuli by whisker trimming did not affect the SD-induced changes in synaptic plasticity. Recovery sleep reversed the effects induced by SD. When SD was combined with moderate stress, LTP induction was not only impaired but also occluded. Both electrophysiological analysis and immunoblotting of purified synaptosomes revealed that an alteration in the molecular composition of synaptically activated NMDA receptors toward a greater NR2A/NR2B ratio accompanied the effects of SD. This change was reversed after recovery sleep. By using an unparalleled, particularly mild form of SD, this study describes a novel approach toward dissociating the consequences of insufficient sleep on synaptic plasticity from nonspecific effects accompanying SD in rodents. We establish a framework for cellular models of cognitive impairment related to sleep loss, a major problem in modern society.
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PMID:Insufficient sleep reversibly alters bidirectional synaptic plasticity and NMDA receptor function. 1713 7

While some species of birds retain the ability to learn new songs as adults, many species can only learn during a restricted period when young. Previous studies have suggested that one potential mechanism of such a limited learning period, an alteration in the composition of postsynaptic NMDA receptors, does not competely block further song learning. Here, we examined whether presynaptic function could play a role in the regulation of learning capacity. We first showed that the participation of NMDA receptor NR2B subunits in synaptic currents in the robust nucleus of the arcopallium (RA), a critical location for integration of signals during song learning by young birds, decreases from young birds to adults. Using release-dependent block of postsynaptic NMDA receptors by an open-channel antagonist to assay presynaptic function, we showed that transmitter release at RA synapses from both HVC and the lateral magnocellular nucleus of the anterior nidopallium systematically decreases during the period of song learning, and in adults is about half that of juveniles. Further, activation of postsynaptic NMDA receptors could induce an acute depression of transmitter release, while lack of exposure to a normal learning environment could delay the developmental reduction in transmitter release. These results suggest that regulation of learning capacity may occur in part by coordination of presynaptic and postsynaptic function.
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PMID:Coordination of presynaptic and postsynaptic maturation in a zebra finch forebrain motor control nucleus during song learning. 1715 10

Ca(2+) influx through NMDA receptors (NMDA-Rs) triggers synaptic plasticity, gene transcription, and cytotoxicity, but little is known about the regulation of NMDA-Rs themselves. We used two-photon glutamate uncaging to activate NMDA-Rs on individual dendritic spines in rat CA1 neurons while we measured NMDA-R currents at the soma and [Ca(2+)] changes in spines. Low-frequency uncaging trains induced Ca(2+)-dependent long-term depression of NMDA-R-mediated synaptic currents. Additionally, uncaging trains caused a reduction in the Ca(2+) accumulation per unit of NMDA-R current in spines due to a reduction in the fraction of the NMDA-R current carried by Ca(2+). Induction of depression of NMDA-R-mediated Ca(2+) influx required activation of NR2B-containing receptors. Receptors in single spines depressed rapidly in an all-or-none manner. These adaptive changes in NMDA-R function likely play a critical role in metaplasticity and in stabilizing activity levels in neuronal networks with Hebbian synapses.
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PMID:Activity-dependent plasticity of the NMDA-receptor fractional Ca2+ current. 1719 27

In order to probe the nature and validity of olfactory bulbectomized (OB) rats as a model of depression, we reevaluated their behavioural and neurochemical deficits in relation to the symptoms and neurochemical abnormalities of depression using our protocols, which distinguish anhedonia-resembling behaviour in sexual behavioural test, the hippocampus (Hip)-dependent long-term memory and anxiety-resembling behaviour specially. Besides exploratory hyperactivity in response to a novel environmental stress resembling the psychomotor agitation, OB rats showed a decrease of libido, and a deficit of long-term explicit memory, resembling loss of interest and cognitive deficits in depressive patients, respectively. OB rats also exhibited the anxiety symptom-resembling behaviour in social interaction and plus-maze tests. In the OB rats, we found degenerated neurons in the piriform cortex, decreased protein expression of NMDA receptor subunit 1 (NR1), but not NR2A or NR2B, in the prefrontal cortex (PFC), Hip and amygdala (Amg), and decreased phosphorylation of cAMP-response element-binding protein (CREB) in the PFC and Hip, but not Amg. The behavioural and neurochemical abnormalities in OB rats, except for the performance in the plus-maze task and neuronal degeneration, were significantly attenuated by repeated treatment with desipramine (10 mg/kg), a typical antidepressant. The present study indicated that OB rats may be a model of depression with comorbid anxiety, characterized by agitation, sexual and cognitive dysfunction, neuronal degeneration, decreased protein expression of NR1, and decreased phosphorylation of CREB.
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PMID:Behavioural and neurochemical features of olfactory bulbectomized rats resembling depression with comorbid anxiety. 1726 34

Spreading depression (SD) has long been associated with the underlying pathophysiology of migraine. Evidence that the N-methyl-D-aspartate (NMDA) glutamate receptor (NMDA-R) is implicated in the generation and propagation of SD has itself been available for more than 15 years. However, to date, there are no reports of NMDA-R antagonists being developed for migraine therapy. In this study, an uncompetitive, pan-NMDA-R blocker, memantine, approved for clinical use, and two antagonists with selectivity for NMDA-R containing the NR2B subunit, (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) and (+/-)-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propanol (Ro 25-6981), were investigated to assess their protective effects against SD in the rat. Under isoflurane anesthesia, d.c. potential and the related cortical blood flow and partial pressure of O2 (pO2) were recorded simultaneously at separate cortical sites. Drugs (1, 3, and 10 mg/kg i.p.) were given 1 h or 30 min before KCl application to the brain surface. Core temperature and arterial pCO2,pO2, and pH measurements confirmed physiological stability. KCl induced 7.7+/-1.8 (mean+/-S.D.) SD events with d.c. amplitude of 14.9+/-2.8 mV. Memantine and CP-101,606 dose-dependently decreased SD event number (to 2.0+/-1.8 and 2.3+/-2.9, respectively) and SD amplitude at doses relevant for therapeutic use. Ro 25-6981 also decreased SD events significantly, but less effectively (to 4.5+/-1.6), without affecting amplitude. These results indicate that NR2B-containing NMDA receptors are key mediators of SD, and as such, memantine- and NR2B-selective antagonists may be useful new therapeutic agents for the treatment of migraine and other SD-related disorders (e.g., stroke and brain injury). Whether chronic, rather than acute, treatment may improve their efficacy remains to be determined.
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PMID:Effects of pan- and subtype-selective N-methyl-D-aspartate receptor antagonists on cortical spreading depression in the rat: therapeutic potential for migraine. 1726 80


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