UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amygdala plays a critical role in fear conditioning, a model of emotional learning and cue-induced anxiety. In the lateral amygdala, fear conditioning is associated with an enduring increase in synaptic strength mediated through AMPA receptors and with a reduction in paired-pulse facilitation, reflecting an increased probability of neurotransmitter release. Here we show that NMDA-mediated transmission in the thalamic-to-lateral amygdala pathway is not facilitated after fear conditioning, although probability of transmitter release is enhanced. Rather, the EC50 for NMDA receptor (NR)-mediated current is shifted threefold to fourfold to the right in fear-conditioned animals, suggesting a postsynaptic alteration in NMDA receptors in the maintenance phase of fear memory. Furthermore, the ability of nonselective and subunit-selective antagonists of NMDA receptors to block NMDA receptor-mediated EPSCs is reduced in lateral amygdala neurons from fear-conditioned animals, suggesting a reduction in NMDA receptors at thalamolateral amygdala synapses. In addition, Western blots show a reduction in phosphorylated-NR1, NR2A, and NR2B subunit protein expression in amygdalas from fear-conditioned animals. These data indicate that postsynaptic mechanisms are involved in synaptic plasticity in the thalamoamygdala pathway in fear conditioning and raise the possibility that: (1) downregulation of the NMDA receptor may protect against excitotoxicity of unchecked NMDA receptor recruitment during induction and consolidation of fear memories, (2) reduced NMDA current and protein may allow persistence of the "capacity to reactivate" amygdala pathways in NMDA receptor-dependent fear memories, or (3) a persistent long-term depression of NMDA transmission may occur after fear learning.
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PMID:NMDA currents and receptor protein are downregulated in the amygdala during maintenance of fear memory. 1461 87

Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2(A) and 5HT1(B) receptors, and dopamine D(5) receptors.
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PMID:Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. 1470 30

Prior studies showed that positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators facilitate long-term potentiation (LTP) and improve the formation of several types of memory in animals and humans. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength. The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) and 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. The third drug was cyclothiazide which potently blocks AMPA receptor desensitization. Effects on plasticity were assessed by measuring (i) the likelihood of obtaining stable potentiation when using theta-burst stimulation with three instead of four pulses per burst, (ii) the maximum amount of potentiation under optimal stimulation conditions, and (iii) the effect on long-term depression (LTD). Both benzamides facilitated the formation of stable potentiation induced with three-pulse burst stimulation which is normally ineffective. CX546 in addition increased maximally inducible potentiation after four-pulse burst stimulation from about 50% to 100%. Burst response analysis revealed that CX546 greatly prolonged the duration of depolarization by slowing the decay of the response which thus presumably leads to a more continuous N-methyl-D-aspartate (NMDA) receptor activation. Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings. CX546, but not CX516, also enhanced nearly two-fold the NMDA receptor-dependent long-term depression induced by heterosynaptic 2 Hz stimulation. Tests with recombinant NMDA receptors (NR1/NR2A) showed that CX516 and CX546 have no direct effects on currents mediated by these receptors. These results suggest that (1) modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, (2) modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and (3) receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus. Taken together, our data indicate that AMPA receptor modulators differ substantially in their ability to enhance synaptic potentiation or depression, depending on their particular influence on receptor kinetics, and hence that they may also be differentially effective in influencing higher-order processes such as memory encoding.
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PMID:Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus. 1475 Dec 92

Cocaine produces multiple neuroadaptations with chronic repeated use. Many of these neuroadaptations can be reversed or normalized by extinction training during withdrawal from chronic cocaine self-administration in rats. This article reviews our past and present studies on extinction-induced modulation of the neuroadaptive response to chronic cocaine in the mesolimbic dopamine system, and the role of this modulation in addictive behavior in rats. Extinction training normalizes tyrosine hydroxylase levels in the nucleus accumbens (NAc) shell, an effect that could help ameliorate dysphoria and depression associated with withdrawal from chronic cocaine use. Extinction training also increases levels of GluR1 and GluR2/3 AMPA receptor subunits, while normalizing deficits in NR1 NMDA receptor subunits, in a manner consistent with long-term potentiation of excitatory synapses in the NAc shell. Our results suggest that extinction-induced increases in AMPA and NMDA receptors may restore deficits in cortico-accumbal neurotransmission in the NAc shell and facilitate inhibitory control over cocaine-seeking behavior. Other changes identified by gene expression profiling, including up-regulation in the AMPA receptor aggregating protein Narp, suggest that extinction training induces extensive synaptic reorganization. These studies highlight potential benefits for extinction training procedures in the treatment of drug addiction.
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PMID:Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration. 1546 21

Growing evidence suggests that NMDA receptor (NMDAR) dysfunction may be involved in schizophrenia. The NMDAR is a multimeric assembly derived from seven different genes (NR1, NR2A-2D and NR3A-3B). While region-specific changes in the expression of most NMDAR subunits have been reported in schizophrenia, possible abnormalities of NR3A expression have not been investigated. Both electrophysiological and anatomical data in rodents, however, suggest that NR3A subunits could play a role in this disorder. In this study, we measured NR3A transcript levels in the dorsolateral prefrontal cortex (DLPFC) and inferior temporal neocortex in the brains of people with schizophrenia, bipolar disorder, depression, and a comparison group. This transcript was elevated by 32% in schizophrenia relative to controls, but only in the DLPFC and not inferior temporal cortical regions. Interestingly, this effect was restricted to gyral aspects of the DLPFC and did not involve sulcal areas. NR3A mRNA was significantly decreased by 12% in bipolar disorder relative to the comparison group in DLPFC, although there were no gyral versus sulcal differences. As was the case in schizophrenia, no changes in NR3A expression were observed in the inferior temporal cortex in bipolar disorder. These data indicate that the NR3A subunit is abnormally expressed in both schizophrenia and bipolar disorder.
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PMID:NR3A NMDA receptor subunit mRNA expression in schizophrenia, depression and bipolar disorder. 1547 7

Brain-derived growth factor (BDNF) acutely regulates synaptic transmission and modulates hippocampal long-term potentiation (LTP) and long-term depression (LTD), cellular models of plasticity associated with learning and memory. Our previous studies revealed that BDNF rapidly increases phosphorylation of NMDA receptor subunits NR1 and NR2B in the postsynaptic density (PSD), potentially linking receptor phosphorylation to synaptic plasticity. To further define molecular mechanisms governing BDNF actions, we examined tyrosine phosphorylation of GluR1, the most well-characterized subunit of AMPA receptors. Initially, we investigated synaptoneurosomes that contain intact pre- and postsynaptic elements. Incubation of synaptoneurosomes with BDNF for 5 min increased tyrosine phosphorylation of GluR1 in a dose-dependent manner, with a maximal, 4-fold enhancement at 10 ng/ml BDNF. NGF had no effects, suggesting the specificity of BDNF actions. Subsequently, we found that BDNF elicited a maximal, 2.5-fold increase in GluR1 phosphorylation in the PSD at 250 ng/ml BDNF within 5 min, suggesting that BDNF enhances the phosphorylation through postsynaptic mechanisms. Activation of trkB receptors was critical as k252-a, an inhibitor of trk receptor tyrosine kinase, blocked the BDNF-activated GluR1 phosphorylation. In addition, AP-5 and MK 801, NMDA receptor antagonists, blocked BDNF enhancement of phosphorylation in synaptoneurosomes or PSDs. Conversely, NMDA, the specific receptor agonist, evoked respective 3.8- and 2-fold increases in phosphorylation in synaptoneurosomes and PSDs within 5 min, mimicking the effects of BDNF. These findings raise the possibility that BDNF modulates GluR1 activity via changes in NMDA receptor function. Moreover, incubation of synaptoneurosomes or PSDs with BDNF and ifenprodil, a specific NR2B antagonist, reproduced the results of AP-5 and MK-801. Finally, coexposure of synaptoneurosomes or PSDs to BDNF and NMDA was not additive, suggesting that BDNF and NMDA activate the same tyrosine phosphorylation site(s) in GluR1. Our findings suggest that BDNF-mediated GluR1 tyrosine phosphorylation potentially regulates synaptic plasticity postsynaptically through NR2B subunits of the NMDA receptor.
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PMID:Brain-derived neurotrophic factor acutely enhances tyrosine phosphorylation of the AMPA receptor subunit GluR1 via NMDA receptor-dependent mechanisms. 1551 88

The NMDA receptor has been implicated in the pathophysiology of several diseases including schizophrenia and affective disorders. We have investigated the NR1 subunit of the NMDA receptor in a well-defined series of psychiatric cases using radioligand binding and quantitative immunoblotting techniques. Saturable radioligand binding of [(3)H]L-689,560 to the glycine site on this subunit of the NMDA receptor was undertaken in superior temporal cortex of patients with schizophrenia, bipolar disorder, depression and matched control subjects. A tendency towards an increased receptor density was found in schizophrenia. A significant decrease in NMDA receptor density below control value was found in both bipolar and depressive disorders. The immunoblotting technique was used to identify NR1 protein in the same series of cases of which two bands were identified consistent with NR1 splice variants. A tendency to a decrease in the density of the NR1 upper band below control values was found in bipolar and depressed patients, but not schizophrenics. Consistent with this observation, the ratio between the upper and lower NR1-immunoreactive bands showed a significant decrease in bipolar disorder, although the ratio in depression did not reach significance. No significant difference was found in the NR1 lower band in any patient group compared with control. The finding of an increase NMDA receptor density in schizophrenia is consistent with the previous reports, with a possible compensatory response to glutamatergic deficits in superior temporal cortex in schizophrenia. The findings in affective disorders are interesting in respect of reports of cortical NMDA receptor deficits in suicide victims, although antidepressant drug treatment may contribute to these changes.
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PMID:The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders. 1553 Nov 11

NR2A and NR2B are the predominant NR2 NMDA receptor subunits expressed in cortex and hippocampus. The relative expression level of NR2A and NR2B is regulated developmentally and these two subunits have been suggested to play distinct roles in long-term synaptic plasticity. We have used patch-clamp recording of recombinant NMDA receptors expressed in HEK293 cells to characterize the activation properties of both NR1/NR2A and NR1/NR2B receptors. Recordings from outside-out patches that contain a single active channel show that NR2A-containing receptors have a higher probability of opening at least once in response to a brief synaptic-like pulse of glutamate than NR2B-containing receptors (NR2A, 0.80; NR2B, 0.56), a higher peak open probability (NR2A, 0.50; NR2B, 0.12), and a higher open probability within an activation (NR2A, 0.67; NR2B, 0.37). Analysis of the sequence of single-channel open and closed intervals shows that both NR2A- and NR2B-containing receptors undergo multiple conformational changes prior to opening of the channel, with at least one of these steps being faster for NR2A than NR2B. These distinct properties produce profoundly different temporal signalling profiles for NR2A- and NR2B-containing receptors. Simulations of synaptic responses demonstrate that at low frequencies typically used to induce long-term depression (LTD; 1 Hz), NR1/NR2B makes a larger contribution to total charge transfer and therefore calcium influx than NR1/NR2A. However, under high-frequency tetanic stimulation (100 Hz; > 100 ms) typically used to induce long-term potentiation (LTP), the charge transfer mediated by NR1/NR2A considerably exceeds that of NR1/NR2B.
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PMID:Subunit-specific gating controls rat NR1/NR2A and NR1/NR2B NMDA channel kinetics and synaptic signalling profiles. 1564 85

Long-term potentiation or depression of synaptic function often requires Ca2+ influx via NMDA-type glutamate receptors (NMDARs) and changes in the autophosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) at Thr286. Autophosphorylated CaMKII binds directly to NMDAR subunits, co-localizes with NMDARs in the postsynaptic density, and phosphorylates NR2B subunits at Ser1303. Here, we demonstrate that CaMKIIalpha enhances the extent and/or rate of desensitization of NMDA-induced macroscopic currents in HEK293 cells co-expressing NR2B with either the NR1(011) or NR1(101) splice variants, without significantly changing other current parameters. In contrast, the extent of desensitization of NMDARs containing NR2A in place of NR2B is significantly decreased by co-expression of CaMKIIalpha. Kinases harboring K42R (inactive kinase) or T286A (autophosphorylation-deficient) mutations are defective in enhancing the desensitization of NR1/NR2B channels. In addition, the CaMKII-dependent enhancement of NR1/NR2B channel desensitization is abrogated by intracellular loading with BAPTA. These data suggest a novel mechanism for Ca2+-dependent negative-feedback regulation of NR2B-containing NMDARs in a CaMKII activity- and autophosphorylation-dependent manner that may modulate NMDAR-mediated synaptic plasticity.
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PMID:CaMKIIalpha enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism. 1586 54

Low levels of the intracellular mediator of glutamate receptor activation, neuronal nitric oxide synthase (nNOS) were previously observed in locus coeruleus (LC) from subjects diagnosed with major depression. This finding implicates abnormalities in glutamate signaling in depression. Receptors responding to glutamate in the LC include ionotropic N-methyl-D-aspartate receptors (NMDARs). The functional NMDAR is a hetero-oligomeric structure composed of NR1 and NR2 (A-D) subunits. Tissue containing the LC and a nonlimbic LC projection area (cerebellum) was obtained from 13 and 9 matched pairs, respectively, of depressed subjects and control subjects lacking major psychiatric diagnoses. NMDAR subunit composition in the LC was evaluated in a psychiatrically normal subject. NR1 and NR2C subunit immunoreactivities in LC homogenates showed prominent bands at 120 and 135 kDa, respectively. In contrast to NRI and NR2C, very weak immunoreactivity of NR2A and NR2B subunits was observed in the LC. Possible changes in concentrations of NR1 and NR2C that might occur in depression were assessed in the LC and cerebellum. The overall amount of NR1 immunoreactivity was normal in the LC and cerebellum in depressed subjects. Amounts of NR2C protein were significantly higher (+ 61%, p = 0.003) in the LC and modestly, but not significantly, elevated in the cerebellum (+ 35%) of depressives as compared to matched controls. Higher levels of NR2C subunit implicate altered glutamatergic input to the LC in depressive disorders.
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PMID:Elevated levels of the NR2C subunit of the NMDA receptor in the locus coeruleus in depression. 1592 Apr 98

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