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 metabotropic glutamate receptors (mGluRs) have many important roles in regulation of neuronal excitability and synaptic transmission. In hippocampal area CA1, activation of mGluRs can reduce both excitatory and inhibitory synaptic transmission. The conventional view is that the presynaptic effects are mediated by L-2-amino-4-phosphonobutyric acid (L-AP4)-sensitive, or group III mGluRs (mGluR4, mGluR6, mGluR7, mGluR8). However, some studies suggest that other mGluR subtypes may also be involved in regulation of excitatory and inhibitory synaptic transmission in area CA1. We have found that two pharmacologically distinct presynaptic receptors are involved in the depression of excitatory transmission at the Schaffer collateral--CA1 synapse. Consistent with previous studies, one receptor subtype is an L-AP4-sensitive receptor that is pharmacologically similar to mGluR4 or mGluR7. However, we have found that a second mGluR subtype, which is pharmacologically similar to mGluR1 and mGluR5 (group I mGluRs), can also reduce excitatory synaptic transmission in area CA1. Analysis of effects of agonists of these two receptors on miniature EPSCs and paired-pulse facilitation suggest that both receptors are localized presynaptically. It is also shown that the mGluR that reduces transmission at inhibitory synapses in area CA1 is presynaptically localized, is insensitive to L-AP4, and is sensitive to agonists selective for mGluR1 and mGluR5.
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PMID:Multiple presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in hippocampal area CA1. 747 45

Long-term depression (LTD) is a well-known form of synaptic plasticity of principal neurons in the mammalian brain. Whether such changes occur in interneurons is still controversial. CA3 hippocampal interneurons expressing Ca2+-permeable AMPA receptors exhibited LTD after tetanic stimulation of CA3 excitatory inputs. LTD was independent of NMDA receptors and required both Ca2+ influx through postsynaptic AMPA receptors and activation of presynaptic mGluR7-like receptors. These results point to the capability of interneurons to undergo plastic changes of synaptic strength through joint activation of pre- and postsynaptic glutamate receptors.
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PMID:Long-term depression in hippocampal interneurons: joint requirement for pre- and postsynaptic events. 1046 2

Glutamatergic neurotransmission has been strongly implicated in the pathophysiology of affective disorders, such as major depression and anxiety. Of all glutamate receptors, the role of group III metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7, mGluR8) in such disorders is the least investigated because of the lack of specific pharmacological tools. To this end, we examined the behavioural profiles of mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) in animal models of depression and anxiety. mGluR7-/- mice were compared with wild-type (mGluR7+/+) littermates and showed substantially less behavioural immobility in both the forced swim test and the tail suspension test. Both behavioural paradigms are widely used to predict antidepressant-like activity. Further, mGluR7-/- mice displayed anxiolytic activity in four different behavioural tests, i.e. the light-dark box, the elevated plus maze, the staircase test, and the stress-induced hyperthermia test, while their cognitive performance was normal in the passive avoidance paradigm. Analysis of locomotor activity in a novel environment demonstrated that mGluR7-/- mice were slightly more active in the initial minutes following placement in the chamber only. Together, these data suggest that mGluR7 may play a pivotal role in mechanisms that regulate behavioural responses to aversive states. Therefore, drugs acting at mGluR7 may provide novel treatments for psychiatric disorders such as depression and anxiety.
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PMID:Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7. 1281 72

We analyzed the subtypes of group III metabotropic glutamate receptors (mGluRs) modulating inhibitory and excitatory transmission in the rat supraoptic nucleus. Bath application of the agonist l-AP4 at 200 microM, a concentration that activates all group III mGluR subtypes, inhibited the frequency but not the amplitude of miniature inhibitory and excitatory postsynaptic currents, indicating a presynaptic site of action. l-AP4 at low concentrations (10 microM), as well as ACPT-1 (50 microM), a specific mGluR III agonist, inhibited transmission at GABAergic and glutamatergic synapses to the same extent as 200 microM l-AP4. Because the potency of l-AP4 and ACPT-1 is much higher on mGluR4 and mGluR8 than on mGluR7, these results are consistent with the presence of high-affinity group III mGluRs regulating transmitter release in this nucleus. In agreement with these findings, DCPG (30 microM), a selective mGluR8 agonist, induced a significant depression of inhibitory and excitatory synaptic currents. Group III mGluRs such as mGluR8, because of their high affinity for glutamate, are particularly well suited to detect small changes in the concentration of this excitatory amino acid in the extracellular space. Their presence, therefore, may favor the negative feedback control exerted by glutamate on its own release as well as the intersynaptic crosstalk mediated by glutamate spillover on adjacent synapses.
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PMID:Regulation of transmitter release by high-affinity group III mGluRs in the supraoptic nucleus of the rat hypothalamus. 1527 22

Regulation of neurotransmission via group-III metabotropic glutamate receptors (mGluR4, -6, -7, and -8) has recently been implicated in the pathophysiology of affective disorders, such as major depression and anxiety. For instance, mice with a targeted deletion of the gene for mGluR7 (mGluR7-/-) showed antidepressant and anxiolytic-like effects in a variety of stress-related paradigms, including the forced swim stress and the stress-induced hyperthermia tests. Deletion of mGluR7 reduces also amygdala- and hippocampus-dependent conditioned fear and aversion responses. Since the hypothalamic-pituitary-adrenal (HPA) axis regulates the stress response we investigate whether parameters of the HPA axis at the levels of selected mRNA transcripts and endocrine hormones are altered in mGluR7-deficient mice. Over all, mGluR7-/- mice showed only moderately lower serum levels of corticosterone and ACTH compared with mGluR7+/+ mice. More strikingly however, we found strong evidence for upregulated glucocorticoid receptor (GR)-dependent feedback suppression of the HPA axis in mice with mGluR7 deficiency: (i) mRNA transcripts of GR were significantly upregulated in the hippocampus of mGluR7-/- animals, (ii) similar increases were seen with 5-HT1A receptor transcripts, which are thought to be directly controlled by the transcription factor GR and finally (iii) mGluR7-/- mice showed elevated sensitivity to dexamethasone-induced suppression of serum corticosterone when compared with mGluR7+/+ animals. These results indicate that mGluR7 deficiency causes dysregulation of HPA axis parameters, which may account, at least in part, for the phenotype of mGluR7-/- mice in animal models for anxiety and depression. In addition, we present evidence that protein levels of brain-derived neurotrophic factor are also elevated in the hippocampus of mGluR7-/- mice, which we discuss in the context of the antidepressant-like phenotype found in those animals. We conclude that genetic ablation of mGluR7 in mice interferes at multiple sites in the neuronal circuitry and molecular pathways implicated in affective disorders.
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PMID:Metabotropic glutamate receptor subtype 7 ablation causes dysregulation of the HPA axis and increases hippocampal BDNF protein levels: implications for stress-related psychiatric disorders. 1623 91

Hippocampal mossy fibers (MFs) innervate CA3 targets via anatomically distinct presynaptic elements: MF boutons (MFBs) innervate pyramidal cells (PYRs), whereas filopodial extensions (Fils) of MFBs innervate st. lucidum interneurons (SLINs). Surprisingly, the same high-frequency stimulation (HFS) protocol induces presynaptically expressed LTP and LTD at PYR and SLIN inputs, respectively. This differential distribution of plasticity indicates that neighboring, functionally divergent presynaptic elements along the same axon serve as autonomous computational elements capable of modifying release independently. Indeed we report that HFS persistently depresses voltage-gated calcium channel (VGCC) function in Fil terminals, leaving MFB VGCCs unchanged despite similar contributions of N- and P/Q-type VGCCs to transmission at each terminal. Selective Fil VGCC depression results from HFS-induced mGluR7 activation leading to persistent P/Q-type VGCC inhibition. Thus, mGluR7 localization to MF-SLIN terminals and not MFBs allows for MF-SLIN LTD expression via depressed presynaptic VGCC function, whereas MF-PYR plasticity proceeds independently of VGCC alterations.
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PMID:Compartmentalized Ca(2+) channel regulation at divergent mossy-fiber release sites underlies target cell-dependent plasticity. 1708 15

At hippocampal mossy fiber (MF)-st. lucidum interneuron (SLIN) synapses, mGluR7 serves as a metaplastic switch controlling bidirectional plasticity. mGluR7 activation during high-frequency stimulation (HFS) triggers presynaptic LTD due to persistent P/Q-type Ca(2+) channel inhibition. However, following mGluR7 internalization HFS produces presynaptic LTP. Surprisingly, LTP is not a simple molecular reversal of Ca(2+) channel depression. Rather, mGluR7 activation/internalization controls plasticity polarity by gating cAMP sensitivity of release. While naive surface mGluR7 expressing MF-SLIN synapses are insensitive to cAMP elevation, synapses that have internalized mGluR7 robustly potentiate following cAMP increases. Moreover, MF-SLIN LTP requires adenylate cyclase (AC) and protein kinase A (PKA) activities. We also discovered an association between mGluR7 and RIM1alpha, an active zone molecule required for AC/PKA-dependent presynaptic LTP. Importantly, the mGluR7-RIM1alpha interaction is regulated by mGluR7 activation, and mice lacking RIM1alpha are deficient in MF-SLIN LTP. We conclude that state-dependent cAMP sensitivity controlled by mGluR7-RIM1alpha interactions underlies MF-SLIN metaplasticity.
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PMID:State-dependent cAMP sensitivity of presynaptic function underlies metaplasticity in a hippocampal feedforward inhibitory circuit. 1910 6

Olfactory bulbectomy (OB) is an established animal model of depression that has been investigated mostly in rats. As in human major depression, OB induces behavioral alterations that can be ameliorated by chronic antidepressant treatment. Furthermore, it was shown that OB induces changes of various protein receptor levels in brain areas that are important in antidepressant therapy. In the present study, we investigated the effects of OB and amitriptyline (AMI) treatment on the expression of metabotropic glutamate receptors (mGluR) in the mouse hippocampus using the western blot method. AMI was given for 14 days, in a dose of 10 mg/kg, intraperitoneally. The levels of most subtypes of mGlu receptors, e.g., mGlu1a (mGluR group I), mGlu2/3 (mGluR group II), mGlu4, and mGlu7 (mGluR group III) receptors, were measured. Additionally, immunohistochemical stainings were made in slices of the mouse hippocampus. It was found that OB induced an increase in mGluR1a-immunoreactivity (IR), which was abolished by AMI treatment in the hippocampus. The removal of the olfactory bulbs caused a decrease in the level of mGlu2/3 receptors in the hippocampus, which was reversed after AMI administration. MGluR4-IR was decreased in the hippocampus in all the groups studied. A decrease of mGluR7-IR was observed in the OB group, and the effect was abolished by the administration of AMI. However, decreases in the level of mGlu2/3 and mGlu7 receptors were observed after AMI administration. The results obtained indicate an influence of OB on mGlu receptors levels in the hippocampus, and the OB-induced effect can be reversed by chronic AMI treatment in the case of mGlu1a, mGlu2/3 and mGlu7 receptors.
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PMID:Olfactory bulbectomy and amitriptyline treatment influences mGlu receptors expression in the mouse brain hippocampus. 1921 76

Metabotropic glutamate receptor 7 (mGluR7) remains the most elusive of the eight known mGluRs primarily because of the limited availability of tool compounds to interrogate its potential therapeutic utility. The discovery of N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082) as the first orally active, brain-penetrable, mGluR7-selective allosteric agonist by Mitsukawa and colleagues (Proc Natl Acad Sci USA 102:18712-18717, 2005) provides a means to investigate this receptor system directly. AMN082 demonstrates mGluR7 agonist activity in vitro and interestingly has a behavioral profile that supports utility across a broad spectrum of psychiatric disorders including anxiety and depression. The present studies were conducted to extend the in vitro and in vivo characterization of AMN082 by evaluating its pharmacokinetic and metabolite profile. Profiling of AMN082 in rat liver microsomes revealed rapid metabolism (t(1/2) < 1 min) to a major metabolite, N-benzhydrylethane-1,2-diamine (Met-1). In vitro selectivity profiling of Met-1 demonstrated physiologically relevant transporter binding affinity at serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (323, 3020, and 3410 nM, respectively); whereas the parent compound AMN082 had appreciable affinity at NET (1385 nM). AMN082 produced antidepressant-like activity and receptor occupancy at SERT up to 4 h postdose, a time point at which AMN082 is significantly reduced in brain and plasma while the concentration of Met-1 continues to increase in brain. Acute Met-1 administration produced antidepressant-like activity as would be expected from its in vitro profile as a mixed SERT, NET, DAT inhibitor. Taken together, these data suggest that the reported in vivo actions of AMN082 should be interpreted with caution, because they may involve other mechanisms in addition to mGluR7.
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PMID:The metabotropic glutamate receptor 7 allosteric modulator AMN082: a monoaminergic agent in disguise? 2150 84

Studies by Breen et al. and Pergadia et al. find evidence for genetic linkage between major depressive disorder and the same region on chromosome 3. The linked region contains the gene GRM7, which encodes a protein for the metabotropic glutamate receptor 7 (mGluR7). Both studies used affected sibling pairs, and neither was able to replicate its finding using association studies in individuals from larger population-based studies. Other family-based studies have also failed to find a signal in this region. Furthermore, there are some differences in how the phenotype was classified, with Breen et al. finding evidence only in the most severely affected patients. Nonetheless, the finding is not without other substantive support. A meta-analysis of 3,957 case subjects with major depressive disorder and 3,428 control subjects from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), Genetics of Recurrent Early-onset Depression (GenRED), and the Genetic Association Information Network-MDD (GAIN-MDD) data sets demonstrated a region of association for major depressive disorder within GRM7. Thus, the significance of this finding remains uncertain, although it points to a gene that might hold significant promise for further developments in studying the pathophysiology and treatment of major depressive disorder.
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PMID:A new lead from genetic studies in depressed siblings: assessing studies of chromosome 3. 2157 67


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