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)

Excitatory amino acid transporters (EAATs) are believed to limit extracellular glutamate concentrations with specific roles poorly understood. At cerebellar climbing fiber-Purkinje cell synapse, EAAT4 and metabotropic glutamate receptor 1 (mGluR1) are closely expressed in surrounding postsynaptic locations, suggesting that EAAT4 may regulate mGluR1 activation. We examined the actions of EAAT4 on synaptic plasticity by applying blockers of glutamate transporters, DL-threo-beta-benzyloxyaspartic acid and D-aspartate. Inhibition of EAAT4 markedly prolonged AMPA receptor-mediated excitatory postsynaptic currents evoked by stimulating climbing fibers. Impairing glutamate uptake facilitated mGluR1-dependent climbing fiber-Purkinje cell synaptic long-term depression (LTD). Glutamate uptake blockers also sufficiently rescued climbing fiber-Purkinje cell synaptic LTD that failed to be induced by a weaker tetanus. Our results suggest that neuronal glutamate transporters strongly influence mGluR1-dependent cerebellar LTD.
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PMID:Blockade of glutamate transporters facilitates cerebellar synaptic long-term depression. 1928 26

Glutamate is the principal neurotransmitter at the primary sensory afferent synapse in the medulla for the taste system. At this synapse, glutamate activates N-methyl-D-aspartate (NMDA) and non-NMDA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and kainate) ionotropic receptors to effect a response in the second-order neurons. The current experiment is the first to examine the role of metabotropic glutamate receptors (mGluRs) in the transmission of taste information. In an in vitro slice preparation of the primary vagal gustatory nucleus in goldfish, primary gustatory afferent fibers were stimulated electrically, whereas evoked dendritic field potentials were recorded in the sensory layers. Recordings were made before, during, and after bath application of mGluR agonists for various mGluR groups and subtypes. Whereas L-AP4, a group III agonist, reduced the field potential, group I and group II agonists had no effect. Furthermore, the selective mGluR4 agonist ACPT-III and mGluR8 agonist PPG were effective at reducing the field potential, whereas agonists selective for mGluR6 and 7 were not. MAP4, a group III mGluR antagonist, attenuated frequency-dependent depression, indicating that endogenous glutamate binds to presynaptic mGluRs under normal conditions. Furthermore, polymerase chain reaction showed that mRNA for mGluR4 and 8 is expressed in the vagal ganglia, a prerequisite if those receptors are expressed presynaptically in the vagal lobe. Collectively, these experiments indicate that mGluR4 and 8 are presynaptic at the primary gustatory afferent synapse and that their activation inhibits glutamatergic release.
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PMID:Group III metabotropic glutamate receptors (mGluRs) modulate transmission of gustatory inputs in the brain stem. 1936 63

Glutamate is the most widely distributed and a major excitatory neurotransmitter in the CNS. It has been found to play a critical role in various physiological functions in which increased glutamate or its subsequent stimulation is thought to have a role in pathophysiological mechanism of various CNS diseases like epilepsy, stroke, depression and pain. Early attempts to develop glutamatergic antagonists failed in clinical studies due to nonselective or competitive antagonism and have a lot of safety issues like loss of cognitive functions, psychomimetic effect and sedation. Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. At present, there are very few effective therapies for neuropathic pain. The current approach includes targeting specific or alternate binding sites of glutamate receptors, resulting in reduced CNS liabilities. Targeting the glutamatergic system shows a better efficacy and fewer side effects, compared with classical drugs for the treatment of neuropathic pain. This review discusses the various targets on glutamatergic system, which includes the receptors, transporters and enzymes, for the treatment of neuropathic pain and their advantages over classical glutamatergic antagonists. The review also highlights the newer drugs in clinical trials for neuropathic pain.
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PMID:Current approaches with the glutamatergic system as targets in the treatment of neuropathic pain. 1953 98

Glutamate transporters play a critical role in the maintenance of low extracellular concentrations of glutamate, which prevents the overactivation of post-synaptic glutamate receptors. Four distinct glutamate transporters, GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3 and EAAT4, are distributed in the molecular layer of the cerebellum, especially near glutamatergic synapses in Purkinje cells (PCs). This review summarizes the current knowledge about the differential roles of these transporters at excitatory synapses of PCs. Data come predominantly from electrophysiological experiments in mutant mice that are deficient in each of these transporter genes. GLAST expressed in Bergmann glia contributes to the clearing of the majority of glutamate that floods out of the synaptic cleft immediately after transmitter release from the climbing fibre (CF) and parallel fibre (PF) terminals. It is indispensable to maintain a one-to-one relationship in synaptic transmission at the CF synapses by preventing transcellular glutamate spillover. GLT-1 plays a similar but minor role in the uptake of glutamate as GLAST. Although the loss of neither GLAST nor GLT-1 affects cerebellar morphology, the deletion of both GLAST and GLT-1 genes causes the death of the mutant animal and hinders the folium formation of the cerebellum. EAAT4 removes the low concentrations of glutamate that escape from uptake by glial transporters, preventing the transmitter from spilling over into neighbouring synapses. It also regulates the activation of metabotropic glutamate receptor 1 (mGluR1) in perisynaptic regions at PF synapses, which in turn affects mGluR1-mediated events including slow EPSCs and long-term depression. No change in synaptic function is detected in mice that are deficient in EAAC1.
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PMID:Functions of glutamate transporters in cerebellar Purkinje cell synapses. 1958 2

Recent studies have indicated that glutamatergic transmission may be altered in bipolar disorder and affected by chronic treatment with mood-stabilizing drugs. Kainate receptors may be of special interest because i) they have a modulatory role in synaptic transmission, long-term potentiation (LTP) and long-term depression (LDP); and ii) involvement of the kainate receptor subunit GluK2 (GluR6) in behavioral symptoms thought characteristic of mania has been demonstrated in knock-out mice. Glutamate receptors are expressed not only on neurons, but also on astrocytes, where they contribute to regulation of synaptic activity. We have previously shown that primary cultures of mouse astrocytes respond to chronic but not acute treatment with therapeutic relevant concentrations of any of the 'classical' mood-stabilizing drugs, lithium ion (Li(+)), carbamazepine or valproate, with changes in uptake of myo-inositol, cPLA(2) expression and intracellular pH. In the present work, we found i) similar gene expression of the GluK2 subunit of the kainate receptor family in primary cultures of mouse astrocytes and in brain in vivo; ii) a reduction of mRNA and protein expression of GluK2 in astrocytes and in brain after chronic treatment with carbamazepine but no effect in neurons; iii) similar down-regulation in astrocytes by oxcarbamazepine, valproic acid or Li(+), which all have mood-stabilizing effect, but not by the anti-convulsant topiramate, which has no such activity; and iv) abrogation of a normally occurring glutamate-induced ERK phosphorylation in the cultured astrocytes after chronic treatment with any of the mood-stabilizing drugs mentioned above. Possible relationships between these and previously demonstrated effects are discussed.
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PMID:Down-regulation of GluK2 kainate receptor expression by chronic treatment with mood-stabilizing anti-convulsants or lithium in cultured astrocytes and brain, but not in neurons. 1959 62

P2X7 purinergic receptors have been implicated in chronic neuropathic and neuroinflammatory pain as well as in depression. These receptors are predominantly found in the central nervous system on microglial cells and on glutamatergic nerve terminals. Here, we develop hypotheses concerning mechanisms by which transient high-frequency impulse firing in glutamatergic terminals, such as occurs in nociceptor terminals accompanying neuropathic/neuroinflammatory pain, can lead to long-lasting changes in neural network function that is mediated by surrounding glial cells. The hypothesis consists of two parts. In the first, glutamate released by low-frequency (2Hz) terminal action potentials is insufficient to generate postsynaptic action potentials, but these are generated by brief high-frequency input bursts. Glutamate released by these bursts is partly removed by transporters on the enveloping astrocyte processes and also excites AMPA receptors on these processes, which then release ATP. This ATP is partly metabolised to adenosine, which acts on presynaptic A1 receptors to inhibit glutamate release. The remaining ATP acts on the presynaptic P2X7 receptors to facilitate glutamate release by both the high-frequency burst of action potentials as well as by a continuous low-frequency (2Hz) action potential firing that occurs in the absence of a neuropathic/neuroinflammatory insult. The positive feedback of terminal glutamate release, triggering astrocyte ATP release and leading to further glutamate release through activation of P2X7 receptors, is then sufficient to allow the normal low-frequency (2Hz) action potentials to now elicit postsynaptic action potentials after the insult is removed. In the second part of this model, the high concentration of ATP derived from astrocytes at the terminal attracts microglia by chemotaxis. The P2X7 receptors on these microglia are then engaged, resulting in microglia secreting the cytokine TNFalpha. This acts on postsynaptic TNF-R1 receptors to increase the number of AMPA receptors there, thus enhancing the efficacy of synaptic transmission. The TNFalpha also acts on presynaptic TNF-R1 to increase the amount of glutamate released by each nerve terminal impulse. Experimental tests can be made of this hypothesis that P2X7 receptors on the presynaptic terminal and those on the microglia synergistically act to ensure feedback pathways that reset to a high level the efficacy of synaptic transmission, thus ensuring chronic neuropathic/neuroinflammatory pain even when the initial insult has subsided.
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PMID:P2X7 regenerative-loop potentiation of glutamate synaptic transmission by microglia and astrocytes. 1964 12

Glutamate transporters are responsible for clearing synaptically released glutamate from the extracellular space. By this action, they maintain low levels of ambient glutamate, thus preventing excitotoxic damage, and contribute to shaping synaptic currents. We show that up-regulation of the glutamate transporter GLT-1 by ceftriaxone severely impaired mGluR-dependent long-term depression (LTD), induced at rat mossy fibre (MF)-CA3 synapses by repetitive stimulation of afferent fibres. This effect involved GLT-1, since LTD was rescued by the selective GLT-1 antagonist dihydrokainate (DHK). DHK per se produced a modest decrease in fEPSP amplitude that rapidly regained control levels after DHK wash out. Moreover, the degree of fEPSP inhibition induced by the low-affinity glutamate receptor antagonist gamma-DGG was similar during basal synaptic transmission but not during LTD, indicating that in ceftriaxone-treated rats LTD induction did not alter synaptic glutamate transient concentration. Furthermore, ceftriaxone-induced GLT-1 up-regulation significantly reduced the magnitude of LTP at MF-CA3 synapses but not at Schaffer collateral-CA1 synapses. Postembedding immunogold studies in rats showed an increased density of gold particles coding for GLT-1a in astrocytic processes and in mossy fibre terminals; in the latter, gold particles were located near and within the active zones. In both CEF-treated and untreated GLT-1 KO mice used for verifying the specificity of immunostaining, the density of gold particles in MF terminals was comparable to background levels. The enhanced expression of GLT-1 at release sites may prevent activation of presynaptic receptors, thus revealing a novel mechanism by which GLT-1 regulates synaptic plasticity in the hippocampus.
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PMID:Up-regulation of GLT-1 severely impairs LTD at mossy fibre--CA3 synapses. 1979 7

Glutamate is the primary excitatory neurotransmitter of the human brain, and recent findings suggest a role for the glutamatergic system in the pathophysiology and treatment of mood disorders. Single proton magnetic resonance spectroscopy (1H-MRS) was used to study the relative in vivo levels of brain neural metabolites. We evaluated the effect of antidepressant treatments on the relative concentration of unresolved glutamate and glutamine (Glx) with GABA contamination (2.35 ppm peak) using single voxel 1H-MRS at 3.0 Tesla. We studied 19 inpatients (7 males, 12 females) affected by bipolar disorder type I, current depressive episode without psychotic features, before and after 1 week of treatment with repeated total sleep deprivation (TSD) combined with light therapy (LT). Chronobiological treatment caused a significant amelioration in mood levels. Changes in the brain Glx/creatine ratio followed a general trend toward decrease, with individual variability. We observed that the decrease in the Glx/creatine ratio significantly correlated with the improvement of both objective and subjective measures of depression.
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PMID:Spectroscopic correlates of antidepressant response to sleep deprivation and light therapy: a 3.0 Tesla study of bipolar depression. 1968 64

Glutamate AMPA receptors are critical for sensory transmission at the spinal cord dorsal horn (DH). Plasma membrane AMPA receptor endocytosis that can be induced by insulin may underlie long term modulation of synaptic transmission. Insulin receptors (IRs) are known to be expressed on spinal cord DH neurons, but their possible role in sensory transmission has not been studied. In this work the effect of insulin application on fast excitatory postsynaptic currents (EPSCs) mediated by AMPA receptors evoked in DH neurons was evaluated. Acute spinal cord slices from 6 to 10 day old mice were used to record EPSCs evoked in visually identified superficial DH neurons by dorsal root primary afferent stimulation. AMPA EPSCs could be evoked in all of the tested neurons. In 75% of the neurons the size of the AMPA EPSCs was reduced to 62.1% and to 68.9% of the control values when 0.5 or 10 microM insulin was applied. There was no significant change in the size of the AMPA EPSCs in the remaining 25% of DH neurons. The membrane permeable protein tyrosine kinase inhibitor, lavendustin A (10 microM), prevented the insulin induced AMPA EPSC depression. Our results suggest a possible role of the insulin pathway in modulation of sensory and nociceptive synaptic transmission in the spinal cord.
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PMID:Modulation of AMPA excitatory postsynaptic currents in the spinal cord dorsal horn neurons by insulin. 2000 24

Glutamate can control inhibitory synaptic transmission through activation of presynaptic kainate receptors. We found that glutamate released by train stimulation of Schaffer collaterals could lead to either short-term depression or short-term facilitation of inhibitory synaptic transmission in mouse CA1 pyramidal neurons, depending on the presence of cannabinoid type 1 (CB(1)) receptors on GABAergic afferents. The train-induced depression of inhibition (t-Di) required the mobilization of 2-arachidonoylglycerol through postsynaptic activation of metabotropic glutamate receptors and [Ca(2+)] rise. GluK1 (GluR5)-dependent depolarization of GABAergic terminals enabled t-Di by facilitating presynaptic CB(1) signaling. Thus, concerted activation of presynaptic CB(1) receptors and kainate receptors mediates short-term depression of inhibitory synaptic transmission. In contrast, in inhibitory connections expressing GluK1, but not CB(1), receptors, train stimulation of Schaffer collaterals led to short-term facilitation. Thus, activation of kainate receptors by synaptically released glutamate gates presynaptic CB(1) signaling, which in turn controls the direction of short-term heterosynaptic plasticity.
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PMID:Synaptic activation of kainate receptors gates presynaptic CB(1) signaling at GABAergic synapses. 2008 51


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