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)

Metabotropic glutamate receptor 5 (mGluR5) plays a critical role in psychostimulant-induced behavior, yet it is unclear whether mGluR5 is activated by psychostimulant administration, or whether its role is constitutive. We previously reported that activation of mGluR5 with the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) can induce a long-term depression (DHPG-LTD) of glutamatergic transmission in the bed nucleus of the stria terminalis (BNST), and that ex vivo induction of this LTD is disrupted by repeated in vivo administration of cocaine. Here we demonstrate that DHPG-LTD is not maintained by alterations in glutamate release, and that postsynaptic endocytosis is necessary. Furthermore, we find that a single administration of cocaine produces a transient disruption of DHPG-LTD, and the duration of this disruption was increased by repeated days of cocaine administration. The disruption produced by cocaine was not permanent, because DHPG-LTD could be induced 10 d after cocaine administration. To test the role of mGluR5 in vivo in the cocaine-induced disruption of DHPG-LTD, we injected mice with the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine before cocaine. mGluR5 antagonism during in vivo cocaine administration rescued subsequent ex vivo induction of DHPG-LTD. The effects of in vivo cocaine could be mimicked by application of cocaine to BNST-containing slices, suggesting that the actions of cocaine are local. Thus, using a novel strategy of in vivo antagonist-induced rescue of ex vivo agonist effects for the same receptor, we provide evidence suggesting that mGluR5 activation is actively recruited by in vivo cocaine.
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PMID:In vivo metabotropic glutamate receptor 5 (mGluR5) antagonism prevents cocaine-induced disruption of postsynaptically maintained mGluR5-dependent long-term depression. 1878 6

In this study we evaluated the effects of the novel, potent non-competitive metabotropic glutamate receptor (mGluR) 1 antagonist (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on (BAY 36-7620) on different types of synaptic plasticity in the hippocampal cornu ammonis (CA) 1-region and on hippocampus-dependent spatial learning. After having confirmed the presence of mGluR1 in the hippocampal CA1 region of our rat strain by confocal microscopy, we tested the effects of BAY 36-7620 on: 1) long-term potentiation (LTP) induced by weak and strong stimulation; 2) 3,5-dihydroxyphenylglycine (DHPG, 30 microM)-induced depression of synaptic transmission; and 3) learning of the hidden platform version of the water maze by mice. BAY 36-7620 (10 microM) amplified LTP but, like the mGluR1 antagonists 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt, 10 microM) and 4-carboxyphenylglycine (4-CPG, 50 microM), diminished LTP at 1 microM. The mGluR5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP, 10 microM) had no effect. BAY 36-7620 (10 microM) did not affect strong LTP. Thus, mGlu 1, but not mGlu 5, receptors modulate LTP elicited by weak stimulation in vitro. DHPG-induced depression of synaptic transmission was only marginally affected by BAY 36-7620 (1 microM) or 4-CPG (100 microM). In a mouse water maze study, BAY 36-7620 (10 mg/kg, i.v.) increased the escape latency and impaired water escape task acquisition during the first 4 days. Drug- and vehicle-treated groups showed comparable performance at day 5. Our data support a role for mGluR1 in LTP and in the acquisition of spatial memory.
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PMID:The potent non-competitive mGlu1 receptor antagonist BAY 36-7620 differentially affects synaptic plasticity in area cornu ammonis 1 of rat hippocampal slices and impairs acquisition in the water maze task in mice. 1883 15

The mechanisms underlying group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) of N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic currents (EPSCs(NMDAR)) are poorly understood. Here we investigated the effects of (R,S)-3,5-dihydroxyphenylglycine (DHPG), a selective agonist of group I mGluRs, on the EPSCs(NMDAR) in area CA1 of acute hippocampal slices from 6- to 8-wk Sprague-Dawley rats. DHPG acutely and persistently depressed the isolated EPSC(NMDAR) and transiently slowed its decay rate. Combined antagonism of mGluR1 and mGluR5 blocked the effects of DHPG. Strong calcium buffering with intracellular BAPTA did not reduce the acute depression or LTD, making the involvement of elevated postsynaptic calcium unlikely. The acute depression and LTD were not mediated by activation of tyrosine kinases or phosphatases, nor were they dependent on protein synthesis. However, the LTD was prevented by the intracellular actin-stabilizer jasplakinolide, raising the possibility that it was associated with a lateral movement of NMDARs. Supporting this hypothesis, when the effective spatial spread of synaptically released glutamate was increased using the glutamate transporter inhibitor TBOA, the resultant EPSC(NMDAR) did not undergo LTD in response to DHPG. Importantly, isolation of the extrasynaptic EPSC(NMDAR) by blockade of synaptic NMDARs with MK-801 showed that this was not due to a potentiation of the preexisting extrasynaptic component. These findings indicate that LTD of NMDAR-mediated synaptic transmission occurs via lateral movement of receptors away from the synapse.
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PMID:Mechanisms of group I mGluR-dependent long-term depression of NMDA receptor-mediated transmission at Schaffer collateral-CA1 synapses. 1910 58

Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.
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PMID:N-Acetylcysteine reverses cocaine-induced metaplasticity. 1913 71

Metabotropic glutamate receptors (mGluRs) are involved in many forms of neuronal plasticity. In the hippocampus, they have well-defined roles in long-lasting forms of both synaptic and intrinsic plasticity. Here, we describe a novel form of long-lasting intrinsic plasticity that we call (S)-3,5-dihydroxyphenylglycine (DHPG)-mediated long-term depression of excitability (DHPG-LDE), and which is generated following transient pharmacological activation of group I mGluRs. In extracellular recordings from hippocampal slices, DHPG-LDE was expressed as a long-lasting depression of antidromic compound action potentials (cAPs) in CA1 or CA3 cells following a 4-min exposure to the group I mGluR agonist (S)-DHPG. A similar phenomenon was also seen for orthodromic fibre volleys evoked in CA3 axons. In single-cell recordings from CA1 pyramids, DHPG-LDE was manifest as persistent failures in antidromic action potential generation. DHPG-LDE was blocked by (S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), an antagonist of mGluR1, but not 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 inhibitor. Although insensitive to antagonists of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate/kainate and gamma-aminobutyric acid(A) receptors, DHPG-LDE was blocked by antagonists of N-methyl-D-aspartate (NMDA) receptors. Similarly, in single-cell recordings, DHPG-mediated antidromic spike failures were eliminated by NMDA receptor antagonism. Long after (S)-DHPG washout, DHPG-LDE was reversed by mGluR1 antagonism. A 4-min application of (S)-DHPG also produced an NMDA receptor-dependent persistent depolarization of CA1 pyramidal cells. This depolarization was not solely responsible for DHPG-LDE, because a similar level of depolarization elicited by raising extracellular K(+) increased the amplitude of the cAP. DHPG-LDE did not involve HCN channels or protein synthesis, but was eliminated by blockers of protein kinase C or tyrosine phosphatases.
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PMID:Metabotropic glutamate receptor 1 activity generates persistent, N-methyl-D-aspartate receptor-dependent depression of hippocampal pyramidal cell excitability. 1949 24

In the intact adult animal, synaptic plasticity in the visual cortex (VC) is a dynamic and naturalistic phenomenon, the mechanisms of which are not yet fully understood. Given its intrinsic role in hippocampal plasticity, we investigated the eVects of pharmacological antagonism of mGluR5 on synaptic plasticity and receptor expression in the VC of freely moving adult pigmented rats, and compared this with hippocampal effects. Persistent long-term potentiation (LTP, >24 h) in layer II/III of the primary VC, and LTP in the dentate gyrus, were impaired by application of the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP). Long-term depression in VC was unaffected. Twenty-four hours after MPEP treatment, mGluR1a monomer expression was reduced in the VC but not in the hippocampus, whereas dimer expression was unaffected; mGluR2/3 and mGluR5 monomers were unaffected, but dimers were reduced in the VC. Our data suggest that mGluR5 is engaged in the regulation of synaptic plasticity in the adult VC and hippocampus: the mechanisms for this may be quite distinct, however. While only LTP is affected by mGluR5-antagonism in the VC, both LTP and LTD are affected in the hippocampus. Furthermore, the higher sensitivity of mGluR expression to antagonism of mGluR5 in VC compared to the hippocampus suggests that mGluR5 regulates plasticity phenomena in these structures by means of distinct mGluR-dependent processes.
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PMID:Synaptic plasticity in the adult visual cortex is regulated by the metabotropic glutamate receptor, mGluR5. 1967 84

Metabotropic glutamate receptor 5 (mGluR5) is highly expressed in the mammalian central nervous system (CNS). It is involved in multiple physiological functions and is a target for treatment of various CNS disorders, including schizophrenia. We report that Norbin, a neuron-specific protein, physically interacts with mGluR5 in vivo, increases the cell surface localization of the receptor, and positively regulates mGluR5 signaling. Genetic deletion of Norbin attenuates mGluR5-dependent stable changes in synaptic function measured as long-term depression or long-term potentiation of synaptic transmission in the hippocampus. As with mGluR5 knockout mice or mice treated with mGluR5-selective antagonists, Norbin knockout mice showed a behavioral phenotype associated with a rodent model of schizophrenia, as indexed by alterations both in sensorimotor gating and psychotomimetic-induced locomotor activity.
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PMID:Norbin is an endogenous regulator of metabotropic glutamate receptor 5 signaling. 2000 3

Long-term depression (LTD) is an important synaptic mechanism for limiting excitatory influence over circuits subserving cognitive and emotional behavior. A major means of LTD induction is through the recruitment of signaling via G(q)-linked receptors activated by norepinephrine (NE), acetylcholine, and glutamate. Receptors from these transmitter families have been proposed to converge on a common postsynaptic LTD maintenance mechanism, such that hetero- and homosynaptic induction produce similar alterations in glutamate synapse efficacy. We report that in the dorsolateral and ventrolateral bed nucleus of the stria terminalis (BNST), recruitment of G(q)-linked receptors by glutamate or NE initiates mechanistically distinct forms of postsynaptically maintained LTD and these LTDs are differentially regulated by stress exposure. In particular, we show that although both mGluR5- and alpha(1)-adrenergic receptor (AR)-dependent LTDs involve postsynaptic endocytosis, the alpha(1)-AR-initiated LTD exclusively involves modulation of signaling through calcium-permeable AMPA receptors. Further, alpha(1)-AR- but not mGluR5- dependent LTD is disrupted by restraint stress. alpha(1)-AR LTD is also impaired in mice chronically exposed to ethanol. These data thus suggest that in the BNST, NE- and glutamate-activated G(q)-linked signaling pathways differentially tune glutamate synapse efficacy in response to stress.
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PMID:Distinct forms of Gq-receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress. 2013 71

Fragile X syndrome (FXS) results from deficiency of fragile X mental retardation protein (FMRP). FXS is the most common heritable form of mental retardation, and is associated with the occurrence of seizures. Factors responsible for initiating FXS-related hyperexcitability are poorly understood. Many protein-synthesis-dependent functions of group I metabotropic glutamate receptors (Gp1 mGluRs) are exaggerated in FXS. Gp1 mGluR activation can mobilize endocannabinoids (eCBs) in the hippocampus and thereby increase excitability, but whether FMRP affects eCBs is unknown. We studied Fmr1 knock-out (KO) mice lacking FMRP to test the hypothesis that eCB function is altered in FXS. Whole-cell evoked IPSCs (eIPSCs) and field potentials were recorded in the CA1 region of acute hippocampal slices. Three eCB-mediated responses were examined: depolarization-induced suppression of inhibition (DSI), mGluR-initiated eCB-dependent inhibitory short-term depression (eCB-iSTD), and eCB-dependent inhibitory long-term depression (eCB-iLTD). Low concentrations of a Gp1 mGluR agonist produced larger eCB-mediated responses in Fmr1 KO mice than in wild-type (WT) mice, without affecting DSI. Western blots revealed that levels of mGluR1, mGluR5, or cannabinoid receptor (CB1R) were unchanged in Fmr1 KO animals, suggesting that the coupling between mGluR activation and eCB mobilization was enhanced by FMRP deletion. The increased susceptibility of Fmr1 KO slices to eCB-iLTD was physiologically relevant, since long-term potentiation of EPSP-spike (E-S) coupling induced by the mGluR agonist was markedly larger in Fmr1 KO mice than in WT animals. Alterations in eCB signaling could contribute to the cognitive dysfunction associated with FXS.
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PMID:Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome. 2041 Jan 24

Associative long-term depression (LTD) in the hippocampus is a form of spike time-dependent synaptic plasticity that is induced by the asynchronous pairing of postsynaptic action potentials and EPSPs. Although metabotropic glutamate receptors (mGluRs) and postsynaptic Ca(2+) signaling have been suggested to mediate associative LTD, mechanisms are unclear further downstream. Here we show that either mGluR1 or mGluR5 activation is necessary for LTD induction, which is therefore mediated by group I mGluRs. Inhibition of postsynaptic phospholipase C, inositol-1,4,5-trisphosphate, and PKC prevents associative LTD. Activation of PKC by a phorbol ester causes a presynaptic potentiation of synaptic responses and facilitates LTD induction by a postsynaptic mechanism. Lithium, an inhibitor of the PKC pathway, inhibits LTD and the presynaptic and postsynaptic effects of the phorbol ester. Furthermore, LTD is sensitive to the postsynaptic application of synthetic peptides that inhibit the interaction of AMPA receptors with PDZ domains, suggesting an involvement of protein interacting with C-kinase 1 (PICK1)-mediated receptor endocytosis. Finally, enhanced PKC phosphorylation, induced by behavioral stress, is associated with enhanced LTD. Both increased PKC phosphorylation and stress-induced LTD facilitation can be reversed by lithium, indicating that this clinically used mood stabilizer may act on synaptic depression via PKC modulation. These data suggest that PKC mediates the expression of associative LTD via the PICK1-dependent internalization of AMPA receptors. Moreover, modulation of the PKC activity adjusts the set point for LTD induction in a behavior-dependent manner.
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PMID:Coincidence detection and stress modulation of spike time-dependent long-term depression in the hippocampus. 2044 48


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