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

We studied how afferent nerve activity affects the in vivo maturation of a fast glutamatergic CNS synapse, the calyx of Held. To address this question, we exploited the distinct presynaptic Ca2+ channel subtypes governing transmitter release at the cochlear inner hair cell (IHC)-spiral neuron synaptic junction compared with those at higher synapses along the auditory pathways. We characterized the functional properties of calyx synapses in wild type (wt) compared with those developing in Ca(V)1.3 subunit-deficient (Ca(V)1.3-/-) mice. Ca(V)1.3-/- mice are deaf because of an absence of glutamate release from IHC, which results in a complete lack of cochlea-driven nerve activity. Presynaptic Ca2+ channel properties, Ca2+ dependence of exocytosis, number of readily releasable quanta, and AMPA mEPSCs were unchanged in postnatal day 14 (P14) to P17 calyx synapses of Ca(V)1.3-/- mice. However, synaptic strength was augmented because presynaptic action potentials were broader, leading to increased quantal release, consistent with lower paired-pulse ratios and stronger depression during repetitive synaptic stimulation. Furthermore, asynchronous release after trains was elevated presumably because of higher residual Ca2+ accumulating in the presynaptic terminals. Finally, we measured larger NMDA EPSCs with higher sensitivity to the NR2B subunit-specific antagonist ifenprodil in P14-P17 synapses of Ca(V)1.3-/- compared with wt mice. These results suggest that auditory activity is required for the adjustment of synaptic strength as well as for the downregulation of synaptic NMDA receptors during postnatal development of the calyx of Held. In contrast, properties of the presynaptic release machinery and postsynaptic AMPA receptors are unaffected by chronic changes in the level of afferent activity at this synapse.
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PMID:The role of physiological afferent nerve activity during in vivo maturation of the calyx of Held synapse. 1730 Nov 80

Some but not other forms of prenatal stress have been shown to impair spatial memory in adult male offspring. It is not clear if this is because of the intensity of the stress, age of rats, or the way in which learning is assessed. We examined the effect of daily varied prenatal stress consisting of 30 min restraint, saline injections and 15 min forced swim on day 17-21 of gestation on spatial learning, synaptic plasticity and the expression of key proteins of the post synaptic density (PSD) in the hippocampus of males aged 4-5 weeks. Prenatal stress impaired spatial learning in the Morris water maze and induced a significant decrease in long-term potentiation (LTP) in hippocampal slices. There was no change in the paired pulse facilitation ratio but there was a significant reduction in the expression of the NR2B subunit of the glutamate type NMDA receptor and the GluR1 subunit of the AMPA receptor, both of which are important modulators of LTP. These changes were accompanied by a remarkable increase in the scaffolding protein PSD95, which interacts with the intracellular carboxy terminal domains of the NR2 subunits. The high levels of PSD95 may have contributed to the impairment of LTP by disrupting the clustering of NMDA receptors in CA1 synapses. The alteration by prenatal stress in the relative amounts of scaffolding proteins and those which compose glutamate receptors could explain the depression of LTP and impairment in the acquisition of spatial learning.
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PMID:Effect of varied gestational stress on acquisition of spatial memory, hippocampal LTP and synaptic proteins in juvenile male rats. 1732 Jan 96

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 contributions of hippocampal long-term depression (LTD) to explicit learning and memory are poorly understood. Electrophysiological and behavioral studies examined the effects of modulating NMDA receptor-dependent LTD on spatial learning in the Morris water maze (MWM). The NMDA receptor co-agonist D-serine substantially enhanced NR2B-dependent LTD, but not long-term potentiation (LTP) or depotentiation, in hippocampal slices from adult wild type mice. Exogenous D-serine did not alter MWM acquisition, but substantially enhanced subsequent reversal learning of a novel target location and performance in a delayed-matching-to-place task. Conversely, an NR2B antagonist disrupted reversal learning and promoted perseveration. Endogenous synaptic D-serine likely saturates during LTP induction because exogenous D-serine rescued deficient LTP and MWM acquisition in Grin1(D481N) mutant mice having a lower D-serine affinity. Thus, D-serine may enhance a form of hippocampal NR2B-dependent LTD that contributes to spatial reversal learning. By enhancing this form of synaptic plasticity, D-serine could improve cognitive flexibility in psychiatric disorders characterized by perseveration of aberrant ideation or behaviors.
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PMID:D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning. 1762 4

Stress and exploration of novel environments induce neural expression of immediate early gene transcription factors (IEG-TFs). However, as yet no IEG-TF has been shown to be required for the normal biological or behavioral responses to these stimuli. Here we show that mice deficient for the IEG-TF early growth response gene (Egr) 3, display accentuated behavioral responses to the mild stress of handling paralleled by increased release of the stress hormone corticosterone. Egr3-/- mice also display abnormal responses to novelty, including heightened reactivity to novel environments and failure to habituate to social cues or startling acoustic stimuli. In a Y-maze spontaneous alternation task, they perform fewer sequential arm entries than controls, suggesting defects in immediate memory. Because stress and novelty stimulate hippocampal long-term depression (LTD), and because abnormalities in habituation to novelty and Y-maze performance have been associated with LTD deficits, we examined this form of synaptic plasticity in Egr3-/- mice. We found that Egr3-/- mice fail to establish hippocampal LTD in response to low frequency stimulation and exhibit dysfunction of an ifenprodil-sensitive (NR1/NR2B) N-methyl-d-aspartate receptor subclass. Long term potentiation induction was not altered. The NR2B-dependent dysfunction does not result from transcriptional regulation of this subunit by Egr3, because NR2B mRNA levels did not differ in the hippocampi of Egr3-/- and control mice. These findings are the first demonstration of the requirement for an IEG-TF in mediating the response to stress and novelty, and in the establishment of LTD.
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PMID:The immediate early gene early growth response gene 3 mediates adaptation to stress and novelty. 1769 71

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


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