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)

Although metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5 are often found to have similar functions, there is considerable evidence that the two receptors also serve distinct functions in neurons. In hippocampal area CA1, mGluR5 has been most strongly implicated in long-term synaptic depression (LTD), whereas mGluR1 has been thought to have little or no role. Here we show that simultaneous pharmacological blockade of mGluR1 and mGluR5 is required to block induction of LTD by the group 1 mGluR agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG). Blockade of mGluR1 or mGluR5 alone has no effect on LTD induction, suggesting that activation of either receptor can fully induce LTD. Consistent with this conclusion, mGluR1 and mGluR5 both contribute to activation of extracellular signal-regulated kinase (ERK), which has previously been shown to be required for LTD induction. In contrast, selective blockade of mGluR1, but not mGluR5, reduces the expression of LTD and the associated decreases in AMPA surface expression. LTD is also reduced in mGluR1 knockout mice confirming the involvement of mGluR1. This shows a novel role for mGluR1 in long-term synaptic plasticity in CA1 pyramidal neurons. In contrast to DHPG-induced LTD, synaptically induced LTD with paired-pulse low-frequency stimulation persists in the pharmacological blockade of group 1 mGluRs and in mGluR1 or mGluR5 knockout mice. This suggests different receptors and/or upstream mechanisms for chemically and synaptically induced LTD.
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PMID:Differential roles for group 1 mGluR subtypes in induction and expression of chemically induced hippocampal long-term depression. 1642 Dec

Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT1A, 5-HT1B, 5-HT1D, 5-HT2C, alpha-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT2C, 5-HT6) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.
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PMID:Innovative approaches for the development of antidepressant drugs: current and future strategies. 1648 68

The bed nucleus of the stria terminalis (BNST) is a key component of the CNS stress and reward circuit. Synaptic plasticity in this region could in part underlie the persistent behavioral alterations in generalized anxiety and addiction. Group I metabotropic glutamate receptors (mGluRs) have been implicated in stress, addiction, and synaptic plasticity, but their roles in the BNST are unknown. We find that activation of group I mGluRs in the dorsal BNST induces depression of excitatory synaptic transmission through two distinct mechanisms. First, a combined activation of group I mGluRs (mGluR1 and mGluR5) induces a transient depression that is cannabinoid 1 receptor dependent. Second, as with endocannabinoid-independent group I mGluR long-term depression (LTD) in the adult hippocampus, we find that activation of mGluR5 induces an extracellular signal-regulated kinase (ERK)-dependent LTD. Surprisingly, our data demonstrate that this LTD requires the ERK1 rather than ERK2 isoform, establishing a key role for this isoform in the CNS. Finally, we find that this LTD is dramatically reduced after multiple exposures but not a single exposure to cocaine, suggesting a role for this form of plasticity in the actions of psychostimulants on anxiety and reward circuitries and their emergent control of animal behavior.
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PMID:Extracellular-signal regulated kinase 1-dependent metabotropic glutamate receptor 5-induced long-term depression in the bed nucleus of the stria terminalis is disrupted by cocaine administration. 1655 72

An increasing amount of evidence suggests that the family of nuclear factor kappaB (NF-kappaB) transcription factors plays an important role in synaptic plasticity and long-term memory formation. The present study investigated the regulation of NF-kappaB family members p50, p65/RelA, and c-Rel in the hippocampus in response to metabotropic glutamate receptor (mGluR) signaling. Activation of group I metabotropic glutamate receptors (GpI-mGluRs) with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) resulted in a time-dependent increase in DNA binding activity of p50, p65, and c-Rel in area CA1 of the hippocampus. An antagonist of mGluR5, 2-Methyl-6-(phenylethynyl)pyridine, inhibited the DHPG-induced activation of NF-kappaB, whereas an antagonist of mGluR1, (S)-(+)-alpha-amino-4-carboxy-2-methylbenzeneacetic acid, did not. Using a series of inhibitors, we investigated the signaling pathways necessary for DHPG-induced activation of NF-kappaB and found that they included the phosphatidyl inositol 3-kinase, protein kinase C, mitogen-activated protein kinase kinase, and p38-mitogen-activated protein kinase pathways. To determine the functional significance of mGluR-induced regulation of NF-kappaB, we measured long-term depression (LTD) of Schaffer-collateral synapses in the hippocampus of c-Rel knock-out mice. Early phase LTD was normal in c-rel(-/-) mice. However, late-phase LTD (>90 min) was impaired in c-rel(-/-) mice. The observations of this deficit in hippocampal synaptic plasticity prompted us to further investigate long-term memory formation in c-rel(-/-) mice. c-rel(-/-) mice exhibited impaired performance in a long-term passive avoidance task, providing additional evidence for c-Rel in long-term memory formation. These results demonstrate that the NF-kappaB transcription factor family is regulated by GpI-mGluRs in the hippocampus and that the c-Rel transcription factor is necessary for long-term maintenance of LTD and formation of long-term memory.
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PMID:Regulation of nuclear factor kappaB in the hippocampus by group I metabotropic glutamate receptors. 1667 61

Several lines of evidence have indicated that the deep cerebellar nuclei (DCN) are a site of memory storage for certain forms of motor learning, most notably associative eyelid conditioning. In particular, these experiments, together with network models, have implicated the excitatory glutamatergic synapse between mossy fibers and DCN neurons in this memory trace. However, to date, evidence for persistent use-dependent change in the strength of this synapse has been almost entirely absent. Here, we report that high-frequency burst stimulation of mossy fibers, either alone or paired with postsynaptic depolarization, gives rise to long-term depression (LTD) of the mossy fiber-DCN synapse. This form of LTD is not associated with changes in the paired-pulse ratio and is blocked by loading with a postsynaptic Ca2+ chelator but not by bath application of an NMDA receptor antagonist. Mossy fiber-DCN LTD requires activation of a group I metabotropic glutamate receptor (mGluR) and protein translation. Unlike mGluR/translation-dependent LTD in other brain regions, this form of LTD requires mGluR1 and is mGluR5 independent.
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PMID:Long-term depression at the mossy fiber-deep cerebellar nucleus synapse. 1680 23

Fragile X syndrome is produced by a defect in a single X-linked gene, called Fmr1, and is characterized by abnormal dendritic spine morphologies with spines that are longer and thinner in neocortex than those from age-matched controls. Studies using Fmr1 knockout mice indicate that spine abnormalities are especially pronounced in the first month of life, suggesting that altered developmental plasticity underlies some of the behavioral phenotypes associated with the syndrome. To address this issue, we used intracellular recordings in neocortical slices from early postnatal mice to examine the effects of Fmr1 disruption on two forms of plasticity active during development. One of these, long-term potentiation of intrinsic excitability, is intrinsic in expression and requires mGluR5 activation. The other, spike timing-dependent plasticity, is synaptic in expression and requires N-methyl-d-aspartate receptor activation. While intrinsic plasticity was normal in the knockout mice, synaptic plasticity was altered in an unusual and striking way: long-term depression was robust but long-term potentiation was entirely absent. These findings underscore the ideas that Fmr1 has highly selective effects on plasticity and that abnormal postnatal development is an important component of the disorder.
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PMID:Early postnatal plasticity in neocortex of Fmr1 knockout mice. 1682 30

Treatment with most antidepressants induces expression of the gene coding for brain-derived neurotrophic factor (BDNF) in the hippocampus (and cerebral cortex). Recent data indicate antidepressant-like activity of group I mGlu receptor (mGluR1 and mGluR5) antagonists in animal tests/models. We now report that chronic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGlu5 receptor antagonist, increased hippocampal but reduced cortical BDNF mRNA level (Northern blot). Desipramine, a classic antidepressant, increased BDNF mRNA level in both examined brain regions. This is the first demonstration that an antagonist of mGlu5 receptors, like a majority of well-established antidepressants, induces hippocampal BDNF gene expression. A significance of MPEP ability to reduce cortical BDNF needs further study. Nevertheless, this observation further indicates a potential antidepressant activity of the group I mGlu receptor antagonists in human depression.
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PMID:Effect of MPEP treatment on brain-derived neurotrophic factor gene expression. 1684 18

In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.
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PMID:Intramembrane receptor-receptor interactions: a novel principle in molecular medicine. 1706 51

Numerous studies over the last few years have suggested that modulating the glutamatergic system may be an efficient method to achieve an antidepressant effect. Data suggest that metabotropic glutamate receptors (mGlu receptors), related to long-term, modulatory effects on glutamatergic neurotransmission, may be a good target for the development of new, effective and safe therapeutic drugs to treat several CNS disorders including depression and anxiety. Several potent, selective and systemically active orthosteric and allosteric ligands of specific mGlu receptor subtypes have been discovered and these have been tested as potential antidepressants in models of depression in rodents. The mGluR5 antagonists and group II mGlu receptor antagonists seem to be the most promising compounds with potential antidepressant-like activity; however, the efficacy of mGlu receptor ligands in the clinical setting is still an unanswered question.
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PMID:Are compounds acting at metabotropic glutamate receptors the answer to treating depression? 1710 80

The existence of long-term depression (LTD) in the dentate gyrus of freely moving rats, as well as the contribution of different types of metabotropic glutamate receptors (mGluRs) to this form of plasticity, has been the subject of much debate. Here, we describe two distinct forms of mGluR-dependent hippocampal LTD in the dentate gyrus of freely moving adult rats. LTD, induced by low-frequency stimulation (LFS) of the medial perforant path (LFS-LTD), was prevented by antagonism of the phospholipase C-coupled receptors, mGluR1 but not mGluR5. Chemical LTD, induced by intracerebral application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine, was blocked by antagonism of both mGluR5 and mGluR1. Selective activation of mGluR5, using (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), also led to chemical LTD. To test whether LFS-LTD and chemical LTD share common induction mechanisms, we applied LFS following the induction of chemical LTD by CHPG (CHPG-LTD). Surprisingly, LFS impaired CHPG-LTD. Further analysis revealed that induction of CHPG-LTD led to altered calcium dynamics sufficient for its reversal by LFS. We found that LTD induced by (R,S)-3,5-dihydroxyphenylglycine, but not by CHPG, is impaired by N-methyl-d-aspartate receptor antagonism. Both forms of chemical LTD strongly require calcium influx through L-type voltage-gated calcium channels. This contrasts with previous findings that LFS-LTD in the dentate gyrus is both N-methyl-d-aspartate receptor and voltage-gated calcium channel independent. LFS-LTD and LTD induced by group I mGluR agonists thus appear to comprise distinct forms of LTD that require the activation of specific group I mGluRs and recruit calcium from different sources.
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PMID:Group I metabotropic glutamate receptors enable two distinct forms of long-term depression in the rat dentate gyrus in vivo. 1755 95

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