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)

The induction of synaptic plasticity is known to be influenced by the previous history of the synapse, a process termed metaplasticity. Here we demonstrate a novel metaplasticity in which group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) of synaptic transmission is regulated by previous mGluR activation. In these studies, the group I mGluR-dependent LTD induced by the selective agonist (RS)-3,5-dihydroxyphenylglycine (DHPG-LTD) was inhibited by previous preconditioning brief high-frequency stimulation (HFS), regardless of whether the preconditioning HFS induced long-term potentiation. Blockade of NMDA receptors during the preconditioning HFS did not alter the inhibition of DHPG-LTD by the HFS. However, antagonism of mGluRs during the preconditioning HFS did prevent the inhibition of DHPG-LTD by the HFS. In addition, blocking PKC stimulation during the preconditioning HFS also prevented the inhibitory effect of HFS on DHPG-LTD. The DHPG-LTD itself was not inhibited by blocking PKC stimulation but was inhibited by blocking the p38 mitogen-activated protein kinase (MAPK) pathway. Thus, whereas the DHPG-LTD is mediated via activation of the p38 MAPK pathway, the inhibitory effects of preconditioning HFS on DHPG-LTD are mediated via stimulation of group I/II mGluRs, activation of PKC, and subsequent blocking of the functioning of group I mGluR.
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PMID:Group I metabotropic glutamate receptor (mGluR)-dependent long-term depression mediated via p38 mitogen-activated protein kinase is inhibited by previous high-frequency stimulation and activation of mGluRs and protein kinase C in the rat dentate gyrus in vitro. 1212 73

1. Three novel phenylglycine analogues; (RS)-alpha-methyl-3-chloro-4-phosphonophenylglycine (UBP1110), (RS)-alpha-methyl-3-methoxy-4-phosphonophenylglycine (UBP1111) and (RS)-alpha-methyl-3-methyl-4-phosphonophenylglycine (UBP1112) antagonised the depression of the fast component of the dorsal root-evoked ventral root potential induced by (S)-AP4 with apparent K(D) values of: 7.4+/-2.3, 5.4+/-0.6 and 5.1+/-0.3 micro M (all n=3), respectively. 2. A Schild analysis of the antagonism of (S)-AP4 induced depression of synaptic transmission by UBP1112 revealed a pA(2) value of 5.3 and a slope of 0.81+/-0.26 (n=9). 3. None of the phenylglycines tested were potent antagonists of responses mediated by group II mGlu receptors (apparent K(D) values >480 micro M). UBP1112 when tested at a concentration of 1 mM had little or no activity on (S)-3,5-DHPG-, NMDA-, AMPA- or kainate-induced responses on motoneurones. 4. UBP1110, UBP1111 and UBP1112 are at least 100-fold selective for group III over group I and II mGlu receptors expressed in the spinal cord making them the most potent, selective, antagonists yet tested at (S)-AP4 sensitive receptors in the spinal cord.
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PMID:Phenylglycine derivatives as antagonists of group III metabotropic glutamate receptors expressed on neonatal rat primary afferent terminals. 1292 40

Activation of postsynaptic group 1 metabotropic glutamate receptors (mGluRs) by the agonist DHPG causes a long-term depression (DHPG-LTD) of excitatory transmission in the CA1 region of the hippocampus, as well as causing the release of endocannabinoids from pyramidal cells. As cannabinoid agonists cause a presynaptic inhibition at these synapses and DHPG-LTD is thought to be expressed, at least in part, by a presynaptic mechanism, we examined the possibility that endocannabinoids mediated DHPG-LTD. We find that antagonists of cannabinoid receptors reduce the acute depression induced by DHPG, but have no effect on the lasting depression. Furthermore, both the acute and the lasting effects of DHPG were unaffected in the CB1 knockout mouse. These findings suggest that endocannabinoids, acting on a non-CB1 cannabinoid receptor, contribute to the acute depression but not to DHPG-LTD. Presumably some other retrograde signalling mechanism is responsible for DHPG-LTD.
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PMID:Endocannabinoids contribute to short-term but not long-term mGluR-induced depression in the hippocampus. 1292 27

In hippocampus and other regions, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors are inserted into synapses during long-term potentiation and removed during long-term depression. However, little is known about regulation of AMPA receptor trafficking in the nucleus accumbens (NAc), despite growing evidence that glutamate-dependent forms of plasticity in the NAc contribute to drug addiction. Using postnatal rat NAc cultures and an immunocytochemical method that selectively detects newly internalized GluR1, we studied the regulation of AMPA receptor internalization in NAc neurons by glutamate agonists. Newly internalized GluR1 was detected during 15 or 30 min of incubation at room temperature, indicating a basal rate of GluR1 turnover. The rate of GluR1 internalization was increased by glutamate (50 microM) within 5 min of its addition. Glutamate-induced GluR1 internalization was partially blocked by either an AMPA receptor antagonist (CNQX; 20 microM) or an N-methyl-D-aspartate (NMDA) receptor antagonist (APV; 50 microM). Both NMDA (50 microM) and AMPA (50 microM) increased GluR1 internalization in a Ca(2+)-dependent manner. The NMDA effect was blocked by APV while the AMPA effect was blocked by APV or CNQX. We interpret these findings to suggest that NMDA and AMPA ultimately trigger GluR1 internalization through the same NMDA receptor-dependent pathway. The effect of glutamate was also partially blocked by the group 1 metabotropic glutamate receptor antagonist N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC; 50 microM), while the group 1 agonist 3,5-dihydroxyphenylglycine (DHPG; 50 microM) stimulated GluR1 internalization. These data suggest that AMPA receptors on NAc neurons may be subject to rapid regulation of their surface expression in response to changes in the activity of glutamate inputs from cortical and limbic regions.
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PMID:Stimulation of N-methyl-D-aspartate receptors, AMPA receptors or metabotropic glutamate receptors leads to rapid internalization of AMPA receptors in cultured nucleus accumbens neurons. 1525 76

This study examined whether activation of group I metabotropic glutamate receptors (mGluRs) could modulate synaptic inhibition of spinal motoneurons in the neonatal rat isolated spinal cord. Recurrent inhibitory postsynaptic potentials (IPSPs) generated by Renshaw cells were evoked via antidromic stimulation of motor axon collaterals and recorded intracellularly from lumbar motoneurons. The selective agonist of group I mGluRs DHPG (5 micromol L-1) depressed the recurrent IPSP, an effect prevented by the selective antagonist AIDA (500 micromol L-1). The depression by DHPG was use-independent and could be partly counteracted by increasing stimulus strength. Paired pulse depression observed at <or=50-ms intervals was blocked by DHPG in an AIDA-sensitive manner. These results suggest that, in the presence of DHPG, smaller recurrent IPSPs can contribute to the excitatory action of mGluR activation on spinal networks, including the generation of synchronous oscillations recorded from motoneurons.
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PMID:Activation of group I metabotropic glutamate receptors depresses recurrent inhibition of motoneurons in the neonatal rat spinal cord in vitro. 1599 Oct 27

Group I metabotropic glutamate receptor (mGluR) agonist DHPG reduced nerve cell death caused by their exposure to NMDA ("neuroprotective effect") and attenuated NMDA receptor-mediated currents [Blaabjerg, M., Baskys, A., Zimmer, J., Vawter, M. P., 2003b. Changes in hippocampal gene expression after neuroprotective activation of group I metabotropic glutamate receptors. Brain Research, Molecular Brain Research 117, 196-205.]. In the present study, we used organotypic hippocampal culture preparation to examine specific phospholipase C (PLC) inhibitor U73122 effects on DHPG-induced neuroprotection, changes in excitatory synaptic transmission associated with the neuroprotective DHPG treatment and a role of group I mGluR ligands in neurogenesis. Results show that short (10 min) DHPG treatment did not result in neuroprotection but significantly depressed field synaptic potentials (fEPSP) in the Schaffer collateral-CA1 pathway. The fEPSP depression was not affected by the PLC inhibitor U73122. In contrast, prolonged (2-h) treatment of cultures with DHPG induced a significant protective effect that was blocked by a PLC inhibitor U73122 but not by its inactive analog U73343. Voltage-clamp measurements of spontaneous miniature excitatory post-synaptic currents (EPSCs) recorded in CA1 neurons from cultures treated with DHPG (10 microM, 2 h) showed a significant reduction of the EPSC amplitude in DHPG-treated but not control (untreated) cultures. This reduction was completely abolished by U73122, suggesting a PLC involvement. Since activation of PLC is thought to be associated with cell proliferation, we investigated whether group I mGluR agonist DHPG or subtype antagonists LY367385 and MPEP have an effect on dentate granule cells expressing immature neuronal marker TOAD-64. DHPG (100 microM, 72 h) slightly but not significantly increased the number of TOAD-64 positive cells. The mGluR1 antagonists LY367385 (10 microM, 72 h) markedly decreased the number of TOAD-64 positive cells and mGluR5 antagonist MPEP (1 microM, 72 h) had no effect. These data suggest that (1) prolonged activation of group I mGluRs reduces nerve cell susceptibility to excitotoxic injury in a PLC-dependent manner; (2) this reduction is associated with a PLC-dependent depression of excitatory synaptic transmission; and (3) mGluR1 activation may facilitate neurogenesis.
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PMID:Group I metabotropic glutamate receptors reduce excitotoxic injury and may facilitate neurogenesis. 1602 52

Hippocampal long-term depression (LTD) comprises an activity-dependent weakening of synaptic strength. In this study we compared persistent LTD induced by the group I mGluR agonist, DHPG, or the group III mGluR agonist, AP4, in the dentate gyrus of freely moving rats. The role of protein translation, using the translation inhibitors, anisomycin and emetine, was also investigated. Potentials were evoked from medial perforant path-dentate gyrus granule cell synapses of male Wistar rats by means of chronically implanted electrodes. Immediately after intracerebral (ventricular) application of DHPG or AP4 robust LTD (>24 h) occurred. Paired-pulse analysis during LTD, and application of mGluR antagonists after stabilisation of depression, supported that LTD genuinely occurred and that the depression was not a consequence of persistence of the agonists at the synapse. Application of a protein synthesis inhibitor 2 h prior to DHPG injection inhibited the expression of LTD (from ca. 6 h post-injection) but did not affect LTD induced by AP4. These data highlight differences in chemical LTD elicited by group I and group III mGluRs. Whereas AP4-induced LTD may arise as a result of modulation of presynaptic glutamate release mechanisms, the protein synthesis dependency of DHPG-induced LTD suggests an additional postsynaptic expression mechanism for this phenomenon.
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PMID:Investigations of the protein synthesis dependency of mGluR-induced long-term depression in the dentate gyrus of freely moving rats. 1602 84

Activation of spinal group I metabotropic glutamate receptors (mGluRs) may have antinociceptive or pro-nociceptive effects in different pain models. Pharmacological activation of group I mGluRs leads to long-term depression (LTD) of synaptic strength between Adelta-fibers and neurons in lamina II of spinal dorsal horn of the rat. Here, we studied the signal transduction pathways involved. Synaptic strength between Adelta-fibers and lamina II neurons was assessed by perforated whole-cell patch-clamp recordings in a spinal cord-dorsal root slice preparation of young rats. Bath application of the specific group I mGluR agonist (S)-3,5-dihydroxyphenylglycine [(S)-3,5-DHPG] produced an LTD of Adelta-fiber-evoked responses. LTD induction by (S)-3,5-DHPG was prevented, when intracellular Ca(2+) stores were depleted by thapsigargin or cyclopiazonic acid (CPA). Preincubation with ryanodine to inhibit Ca(2+)-induced Ca(2+) release had no effect on LTD-induction by (S)-3,5-DHPG. In contrast, pretreatment with 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of inositol-1,4,5-trisphosphate (IP(3))-sensitive Ca(2+) stores prevented LTD induction. Preincubation with the specific protein kinase C (PKC) inhibitors bisindolylmaleimide I (BIM) or chelerythrine, respectively, had no effect. Inhibition of L-type VDCCs by verapamil or nifedipine prevented LTD-induction by (S)-3,5-DHPG. The presently identified signal transduction cascade may be relevant to the long-term depression of sensory information in the spinal cord, including nociception.
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PMID:Signal transduction pathways of group I metabotropic glutamate receptor-induced long-term depression at sensory spinal synapses. 1618 11

The aim of this study was to investigate whether synaptic plasticity and metaplasticity in slice cultures of the young rat hippocampus were comparable to previously reported synaptic plasticity and metaplasticity in acute adult hippocampal slices. This is relevant since differences do exist between the preparations as a result of age and the ex vivo maintenance. We prepared and maintained slice cultures from 5- to 6-day-old rats according to the porous membrane method. After 12-16 days in vitro, extracellular low-frequency stimulation (LFS) and high-frequency stimulation (HFS) protocols were applied to the Schaffer collaterals, and extracellular field potentials were recorded in area CA1. LFS and HFS induced long-term depression (LTD) and long-term potentiation (LTP), respectively. LTP could be reversed by LFS, as could LTD by HFS 60 min after induction. Plotting the amount of LTD and LTP versus stimulation protocol demonstrated frequency-dependence of the sign and extent of plasticity. Priming activation of group 1 metabotropic glutamate receptors (mGluRs) with DHPG facilitated subsequent LTP, revealing a metaplastic effect similar to that observed in acute slices. Immunohistochemistry for group 1 mGluR subtypes mGluR1alpha and mGluR5 showed both receptors to be present in these cultures. We conclude that synaptic plasticity and mGluR-mediated metaplasticity are largely comparable to those effects found in acute in vitro techniques.
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PMID:Properties of long-term synaptic plasticity and metaplasticity in organotypic slice cultures of rat hippocampus. 1632 58

Two forms of long-term depression (LTD), triggered by activation of NMDA receptors (NMDARs) and metabotropic glutamate receptors (mGluRs), respectively, can be induced at CA1 synapses in the hippocampus. Compared with NMDAR-LTD, relatively little is known about mGluR-LTD. Here, we show that protein tyrosine phosphatase (PTP) inhibitors, orthovanadate and phenylarsine oxide, selectively block mGluR-LTD induced by application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG-LTD), because NMDAR-LTD is unaffected by these inhibitors. Furthermore, DHPG-LTD measured using whole-cell recording is similarly blocked by either bath-applied or patch-loaded PTP inhibitors. These inhibitors also block the changes in paired-pulse facilitation and coefficient of variation that are associated with the expression of DHPG-LTD. DHPG treatment of hippocampal slices was associated with a decrease in the level of tyrosine phosphorylation of GluR2 AMPA receptor (AMPAR) subunits, an effect blocked by orthovanadate. Finally, in dissociated hippocampal neurons, orthovanadate blocked the ability of DHPG to reduce the number of AMPA receptor clusters on the surface of dendrites. Again, the effects of PTP blockade were selective, because NMDA-induced decreases in surface AMPAR clusters was unaffected by orthovanadate. Together, these data suggest that activation of postsynaptic PTP results in tyrosine dephosphorylation of AMPARs and their removal from the synapse.
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PMID:Tyrosine phosphatases regulate AMPA receptor trafficking during metabotropic glutamate receptor-mediated long-term depression. 1651 Jul 32


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