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)

Recent evidence indicates that arachidonic acid (AA) and its metabolites play a fast messenger role in synaptic modulation in the CNS. 12-Lipoxygenase derivatives are released by Aplysia sensory neurons in response to inhibitory transmitters and directly target a class of K+ channels, increasing the probability of their opening. In this way, hyperpolarization is achieved and action potentials are shortened, leading to synaptic depression. Other types of K+ channels in vertebrate excitable cells have been found to be sensitive to arachidonic acid, lipoxygenase products, and polyunsaturated fatty acids (PUFA). In the mammalian CNS, arachidonic acid is released upon stimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors. We found that arachidonic acid inhibits the rate of glutamate uptake in both neuronal synaptic terminals and astrocytes. Neither biotransformation nor membrane incorporation are required for arachidonic acid to exert this effect. The phenomenon, which is rapid and evident at low microM concentrations of AA, may involve a direct interaction with the glutamate transporter or its lipidic microenvironment on the outer side of the cell membrane. Polyunsaturated fatty acids mimic arachidonate with a rank of potency parallel to the degree of unsaturation. Since the effect of glutamate on the synapses is terminated by diffusion and uptake, a slowing of the termination process may potentiate glutamate synaptic efficacy. However, excessive extracellular accumulation of glutamate may lead to neurotoxicity.
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PMID:A role for the arachidonic acid cascade in fast synaptic modulation: ion channels and transmitter uptake systems as target proteins. 137 92

L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC) reverses plasma membrane glutamate transporters and elevates extracellular glutamate levels in vivo. We investigated the possibility that L-trans-PDC-stimulated glutamate levels are mediated partially by increases in transsynaptic activity. Therefore, the degree to which L-trans-PDC-evoked glutamate levels depend on calcium, sodium-channel activation, and glutamate-receptor activation was investigated by infusing via reverse microdialysis (a) 0.1 mM calcium, (b) 1 microM tetrodotoxin, a selective blocker of voltage-dependent sodium channels, (c) R(-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a selective NMDA-receptor antagonist, or (d) LY293558, a selective alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate antagonist. In separate experimental groups, L-trans-PDC-evoked glutamate levels were reduced significantly by 55% in the presence of 0.1 mM calcium and by 46% in the presence of tetrodotoxin. Additionally, CPP and LY293558 significantly attenuated L-trans-PDC-evoked glutamate levels without altering basal glutamate levels. These data suggest that glutamate transporter reversal by L-trans-PDC initially elevates extracellular glutamate levels enough to stimulate postsynaptic glutamate receptors within the striatum. It is proposed that glutamate-receptor stimulation activates a positive feedback loop within the basal ganglia, leading to further glutamate release from corticostriatal and thalamostriatal afferents. Therefore, either extracellular striatal calcium reduction or tetrodotoxin perfusion leads to decreased action potential-dependent glutamate release from these terminals. In addition, blocking glutamate receptors directly reduces medium spiny neuronal firing and indirectly attenuates corticostriatal and thalamostriatal activity, resulting in an overall depression of L-trans-PDC-stimulated glutamate levels.
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PMID:L-trans-pyrrolidine-2,4-dicarboxylic acid-evoked striatal glutamate levels are attenuated by calcium reduction, tetrodotoxin, and glutamate receptor blockade. 908 26

Cerebellar long-term potentiation (LTP) is a use-dependent increase in the strength of the granule cell-Purkinje neuron synapse that occurs after brief stimulation of granule cell axons at 2-8 Hz. Previous work has shown that cerebellar LTP also may be seen when synaptic currents are evoked in granule cell-glial cell pairs in culture. This finding suggests a model in which cerebellar LTP is expressed presynaptically and therefore may be detected by either neuronal or glial postsynaptic cells. However, synaptic currents evoked in both granule cell-glial cell pairs and granule cell-Purkinje neuron pairs in culture are mediated primarily by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors, raising the possibility that cerebellar LTP might be expressed postsynaptically in both glial cells and Purkinje neurons in a similar manner. To address this question, glutamate transport currents were recorded in granule cell-glial cell pairs in culture by pharmacological isolation. These currents were increased by substitution of internal Cl with NO3 and were blocked by -pyrrolidine-2,4-dicarboxylate, both characteristics of the major cloned Bergmann glial cell glutamate transporter, EAAT1. After acquisition of baseline responses, LTP of isolated transport current was evoked by stimulation at 4 Hz (100 pulses) and could be blocked by removal of external Ca during this stimulation. The expression of LTP was associated with a decrease in the rate of synaptic failures and a decrease in the degree of paired-pulse facilitation. These findings, when taken together with the previous observation that both Purkinje neuron and glial AMPA/kainate responses can be used to detect cerebellar LTP, strongly suggest that the expression of cerebellar LTP is, at least in part, presynaptic. This strategy should also be useful in illuminating the locus of expression of other model systems of information storage such as hippocampal LTP/long-term depression.
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PMID:Synaptically evoked glutamate transport currents may be used to detect the expression of long-term potentiation in cerebellar culture. 963 15

Nitrous oxide (N2O; laughing gas) has been a widely used anesthetic/analgesic since the 19th century, although its cellular mechanism of action is not understood. Here we characterize the effects of N2O on excitatory and inhibitory synaptic transmission in microcultures of rat hippocampal neurons, a preparation in which anesthetic effects on monosynaptic communication can be examined in a setting free of polysynaptic network variables. Eighty percent N2O occludes peak NMDA receptor-mediated (NMDAR) excitatory autaptic currents (EACs) with no effect on the NMDAR EAC decay time course. N2O also mildly depresses AMPA receptor-mediated (AMPAR) EACs. We find that N2O inhibits both NMDA and non-NMDA receptor-mediated responses to exogenous agonist. The postsynaptic blockade of NMDA receptors exhibits slight apparent voltage dependence, whereas the blockade of AMPA receptors is not voltage dependent. Although the degree of ketamine and Mg2+ blockade of NMDA-induced responses is dependent on permeant ion concentration, the degree of N2O blockade is not. We also observe a slight and variable prolongation of GABAA receptor-mediated (GABAR) postsynaptic currents likely caused by previously reported effects of N2O on GABAA receptors. Despite the effects of N2O on both NMDA and non-NMDA ionotropic receptors, glial glutamate transporter currents and metabotropic glutamate receptor-mediated synaptic depression are not affected. Paired-pulse depression, the frequency of spontaneous miniature excitatory synaptic currents, and high-voltage-activated calcium currents are not affected by N2O. Our results suggest that the effects of N2O on synaptic transmission are confined to postsynaptic targets.
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PMID:Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. 982 32

We previously reported a 50% reduction in cortical infarct volume following transient focal cerebral ischemia in rats preconditioned 3 days earlier with cortical spreading depression (CSD). The mechanism of the protective effect of prior CSD remains unknown. Recent studies demonstrate reversal of excitatory amino acid transporters (EAATs) to be a principal cause for elevated extracellular glutamate levels during cerebral ischemia. The present study measured the effect of CSD preconditioning on (a) intraischemic glutamate levels and (b) regulation of glutamate transporters within the ischemic cortex of the rat. Three days following either CSD or sham preconditioning, rats were subjected to 200 min of focal cerebral ischemia, and extracellular glutamate concentration was measured by in vivo microdialysis. Cortical glutamate exposure decreased 70% from 1,772.4 +/- 1,469.2 microM-min in sham-treated (n = 8) to 569.0 +/- 707.8 microM-min in CSD-treated (n = 13) rats (p <0.05). The effect of CSD preconditioning on glutamate transporter levels in plasma membranes (PMs) prepared from rat cerebral cortex was assessed by western blot analysis. Down-regulation of the glial glutamate transporter isoforms EAAT2 and EAAT1 from the PM fraction was observed at 1, 3, and 7 days but not at 0 or 21 days after CSD. Semiquantitative lane analysis showed a maximal decrease of 90% for EAAT2 and 50% for EAAT1 at 3 days post-CSD. The neuronal isoform EAAT3 was unaffected by CSD. This period of down-regulation coincides with the time frame reported for induced ischemic tolerance. These data are consistent with reversal of glutamate transporter function contributing to glutamate release during ischemia and suggest that down-regulation of these transporters may contribute to ischemic tolerance induced by CSD.
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PMID:Preconditioning with cortical spreading depression decreases intraischemic cerebral glutamate levels and down-regulates excitatory amino acid transporters EAAT1 and EAAT2 from rat cerebal cortex plasma membranes. 1089 59

At the cerebellar parallel fiber-Purkinje cell synapse, isolated presynaptic activity induces fast excitatory postsynaptic currents via ionotropic glutamate receptors while repetitive, high-frequency, presynaptic activity can also induce a slow excitatory postsynaptic current that is mediated by metabotropic glutamate receptors (mGluR1-EPSC). Here we investigated the involvement of glutamate uptake in the expression of the mGluR1-EPSC. Inhibitors of glutamate uptake led to a large increase of the mGluR1-EPSC. D-aspartate (0.4 mM) and L(-)-threo-3-hydroxyaspartate (0.4 mM) increased the mGluR1-EPSC approximately 4.5 and approximately 9-fold, respectively, while dihydrokainic acid (1 mM), had no significant effect on the mGluR1-EPSC. D-aspartate (0.4 mM) shifted the concentration-response curve of the depression of the mGluR1-EPSC by the low-affinity mGluR1 antagonist (S)-a-Methyl-4-carboxyphenylglycine [(S)-MCPG] to higher concentrations and decreased the stimulus intensity and the number of necessary stimuli to evoke an mGluR1-EPSC. Depression of the mGluR1-EPSC by rapid pressure application of (S)-MCPG at varying time intervals after tetanic stimulation of the parallel fibers indicated that the glutamate concentration in the peri- and extrasynaptic space decayed with time constants of 36 and 316 ms under control conditions and with inhibition of glutamate uptake, respectively. These results show that expression of the slow mGluR-mediated excitatory postsynaptic current is controlled by glutamate transporter activity. Thus in contrast to fast glutamatergic synaptic transmission, metabotropic glutamate receptor-mediated transmission is critically dependent on the activity and capacity of glutamate uptake.
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PMID:Glutamate uptake controls expression of a slow postsynaptic current mediated by mGluRs in cerebellar Purkinje cells. 1192 16

The presence of group III metabotropic glutamate receptors on GABAergic terminals in the supraoptic nucleus suggests that the level of glutamate in the extracellular space may regulate synaptic strength at inhibitory synapses. To test this hypothesis we examined the consequences of increasing ambient glutamate on GABA-mediated synaptic activity in supraoptic neurons. The concentration of the excitatory amino acid in the extracellular space was increased pharmacologically by blocking glutamate transporters. Inhibition of the astrocyte-specific GLT-1 glutamate transporter led to a reversible decrease in evoked inhibitory postsynaptic current amplitude. This modulation had a presynaptic origin as revealed by analysis of paired-pulse ratio and miniature inhibitory currents. Furthermore, blocking group III metabotropic glutamate receptors with the specific antagonist MAP4 prevented the depression of GABAergic transmission induced by glutamate transporter blockade. Thus, presynaptic metabotropic glutamate receptors located on inhibitory terminals in the supraoptic nucleus appear to sense changes in ambient glutamate and modify GABA release accordingly. However, it seems that such changes need to reach a certain magnitude because the discrete deficit in glutamate clearance which occurs in the supraoptic nucleus of lactating rats is not sufficient to modulate GABA-mediated transmission. These results suggest that ambient glutamate contributes to the modulation of synaptic efficacy not only at glutamatergic synapses but also at inhibitory GABAergic synapses.
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PMID:Modulation of GABAergic transmission by endogenous glutamate in the rat supraoptic nucleus. 1275 76

The aim of this study was to determine the effect of mood disorders, including psychological distress and depression, on stroke outcome. Male Fischer rats were exposed to immobilisation stress, an animal paradigm of psychological stress, major depression and post-traumatic stress disorder. Either a subacute (1 h for 7 days) or a chronic (6 h for 21 days) exposure to stress was applied 24 h before permanent middle cerebral artery occlusion (MCAO). Stroke outcome was assessed by measurement of infarct size and behavioural characterisation. Serum glutamate and brain ATP levels as well as brain glutamate transporter function and expression were studied in the search for the molecular mechanisms involved. Subacute stress exposure increased infarct size and decreased behavioural scores after stroke. On the contrary, chronic stress exposure decreased infarct size. Peak serum glutamate levels correlated with infarct size after MCAO. Expression of glutamate transporters was decreased by subacute stress, whereas the expression of EAAT1, a glial glutamate carrier, was increased after the chronic stress protocol. Our results indicate that distinct patterns of stress determine different stroke outcomes, and that expressional changes of brain glutamate transporters, able to affect glutamate release after stroke, are involved.
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PMID:Effect of subacute and chronic immobilisation stress on the outcome of permanent focal cerebral ischaemia in rats. 1285 May 80

Activation of cannabinoid CB1 receptors reduces glutamatergic synaptic transmission in the rodent striatum and is involved in the normal control of motor function by the basal ganglia. Here we investigated CB1 receptor regulation of glutamate release and uptake and synaptic transmission in the rat striatum. We show that CB1 receptor activation reduces both the release and uptake of [3H]glutamate in striatal slices. We also demonstrate that both activation of CB1 receptors and inhibition of glutamate uptake reduce corticostriatal synaptic transmission in a mutually occlusive manner and that both forms of depression are dependent on metabotropic glutamate receptor (mGluR) activation. We propose that CB1 receptor activation in the striatum decreases glutamate transporter activity and that the resulting increase in synaptic cleft glutamate concentration causes the activation of presynaptic mGluRs, which then decrease glutamate release.
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PMID:Cannabinoids decrease corticostriatal synaptic transmission via an effect on glutamate uptake. 1465 64

Maturation of many synapses of the CNS is characterized by a reduction in initial release probability and associated alterations in short-term plasticity (STP). We investigated the role of tonic activity of metabotropic glutamate receptors (mGluRs) in this process in glutamatergic synapses of rat neocortex. Consistent with previous reports, STP of excitatory postsynaptic currents (EPSCs) evoked by five-pulse stimulation was found to switch from depression at postnatal days 13-17 (P13-17) to facilitation at postnatal days 28-42 (P28-42). (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine, a specific mGluR2/3 agonist, strongly depressed EPSCs both at the early stage and the late stage of cortical development. This was accompanied by a switch from depression to facilitation of STP at the early stage and an increase in facilitation at the late stage. While application of 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl) propanoic acid (LY341495), an mGluR antagonist that is most potent at mGluR2/3, had no significant effect at the early stage, it significantly enhanced EPSC amplitude and reduced short-term facilitation at the late stage. Blocking glutamate transporter activity with l-trans-pyrrolidine-2,4-dicarboxylate (tPDC) significantly reduced EPSC amplitude and short-term depression in the younger group but had no effect in the older specimens. The effect of tPDC was blocked by LY341495. These results suggest that a progressive increase in tonic mGluR activity during postnatal development contributes to a reduction of release probability in excitatory cortical synapses. They also indicate that glutamate transporter activity in the neocortex decreases during postnatal development. This may play a role in increasing tonic activity of mGluRs by increasing ambient glutamate levels in the perisynaptic extracellular space.
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PMID:Tonic activity of metabotropic glutamate receptors is involved in developmental modification of short-term plasticity in the neocortex. 1504 23


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