Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 modulatory action of substance P on synaptic transmission of CA1 neurons was studied using intra- or extracellular recording from the mouse hippocampal slice preparation. Bath-applied substance P (2-4 microM) or the selective NK1 receptor agonist substance P methylester (SPME, 10 nM-5 microM) depressed field potentials (recorded from stratum pyramidale) evoked by focal stimulation of Schaffer collaterals. This effect was apparently mediated via NK1 receptors since it was completely blocked by the selective NK1 antagonist SR 140333. The field potential depression by SPME was significantly reduced in the presence of bicuculline. Intracellular recording from CA1 pyramidal neurons showed that evoked excitatory postsynaptic potentials (EPSPs) and evoked inhibitory postsynaptic potentials (IPSPs) were similarly depressed by SPME, which at the same time increased the frequency of spontaneous GABAergic events and reduced that of spontaneous glutamatergic events. The effects of SPME on spontaneous and evoked IPSPs were prevented by the ionotropic glutamate receptor blocker kynurenic acid. In tetrodotoxin (TTX) solution, no change in either the frequency of spontaneous GABAergic and glutamatergic events or in the amplitude of responses of pyramidal neurons to 4 microM alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or 10 microM N-methyl-D-aspartate (NMDA) was observed. On the same cells, SPME produced minimal changes in passive membrane properties unable to account for the main effects on synaptic transmission. The present data indicate that SPME exerted its action on CA1 pyramidal neurons via a complex network mechanism, which is hypothesized to involve facilitation of a subset of GABAergic neurons with widely distributed connections to excitatory and inhibitory cells in the CA1 area.
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PMID:Modulation by substance P of synaptic transmission in the mouse hippocampal slice. 978 2

We studied how metabotropic glutamate receptor (mGluR) activation modifies the synaptic and intrinsic membrane properties of neonatal rat trigeminal motoneurons using the broad-spectrum mGluR agonist (1S,3R)-1-amino-1,3-cyclopentane-dicarboxylic acid [(1S,3R)-ACPD], group I/II antagonist (+/-)-alpha-methyl-4-carboxy-phenylglycine (MCPG), and group III agonist L-2-amino-4-phosphonobutanoate (L-AP4). (1S,3R)-ACPD depressed excitatory transmission to trigeminal motoneurons presynaptically and postsynaptically via presynaptic inhibition and by reducing the currents carried by ionotropic glutamate receptors selective for AMPA. (1S,3R)-ACPD also depolarized trigeminal motoneurons and increased input resistance by suppressing a Ba2+-sensitive leakage K+ current. These effects were not mimicked by L-AP4 (100-200 microM). High-threshold Ca2+ currents were also suppressed by (1S,3R)-ACPD. Repetitive stimulation of excitatory premotoneurons mimicked the postsynaptic effects of (1S, 3R)-ACPD. The postsynaptic effects of (1S,3R)-ACPD and repetitive stimulation were both antagonized by MCPG, suggesting that mGluRs were similarly activated in both experiments. We conclude that mGluRs can be recruited endogenously by glutamatergic premotoneurons and that mGluR-mediated depression of excitatory transmission, combined with increased postsynaptic excitability, enhances the signal-to-noise ratio of oral-related synaptic input to trigeminal motoneurons during rhythmical jaw movements.
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PMID:Regulation of intrinsic and synaptic properties of neonatal rat trigeminal motoneurons by metabotropic glutamate receptors. 980 61

We sought to determine whether metabotropic glutamate receptors contribute to frequency-dependent depression of vagal and aortic baroreceptor signal transmission in the nucleus of the solitary tract (NTS) in vivo. In alpha-chloralose-anesthetized rabbits, we determined the number of extracellular action potentials synaptically evoked by low (1 Hz)- or high-frequency vagal (3-20 Hz) or aortic depressor nerve (ADN) (6-80 Hz) stimulation and postsynaptically evoked by the ionotropic glutamate receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The metabotropic glutamate receptor agonist (2S,1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) attenuated NTS responses monosynaptically evoked by 1-Hz vagus stimulation by 34% (n = 25; P = 0.011), while augmenting AMPA-evoked responses by 64% (n = 17; P = 0.026). The metabotropic glutamate receptor antagonist alpha-methyl-4-phosphonophenylglycine (MPPG) did not affect NTS responses to low-frequency vagal stimulation (n = 11) or AMPA (n = 10) but augmented responses to high-frequency stimulation by 50% (n = 25; P = 0.0001). MPPG also augmented NTS responses to high-frequency ADN stimulation by 35% (n = 9; P = 0.048) but did not affect responses to low-frequency stimulation (n = 9) or AMPA (n = 7). The results suggest that metabotropic glutamate receptors, presumably at presynaptic sites, contribute to frequency-dependent depression of vagal and aortic baroreceptor signal transmission in NTS.
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PMID:Metabotropic glutamate receptors depress vagal and aortic baroreceptor signal transmission in the NTS. 981 76

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

Synaptic responses mediated by the N-methyl-D-aspartate receptor (NMDAr) and non-NMDAr activation were compared in CA1 hippocampal region of young (3-4 months old) and aged (25-33 months old) Sprague-Dawley rats with the use of ex vivo extracellular recordings techniques. In aged rats, the amplitude of the NMDAr-mediated field excitatory postsynaptic potentials (fEPSPs) was not altered, whereas their duration was significantly increased. In contrast, the magnitude of non-NMDAr-mediated fEPSPs was significantly smaller. The presynaptic fiber volley was not affected by age. Considering that the depression of non-NMDAr-mediated responses was previously attributed to fewer synaptic contacts between glutamatergic afferent fibers and pyramidal cells in aged animals (see Barnes et al., Hippocampus 1992;2:457-468), the absence of age-related changes in the amplitude of NMDAr-mediated fEPSPs suggests that compensatory mechanisms may occur. The contribution of gamma-aminobutyric acid (GABA) and acetylcholine to these mechanisms was addressed. The NMDAr-mediated fEPSPs were then recorded (1) in young and aged rats before and after blockade of the GABA(B) receptor-mediated inhibition by the specific antagonist CGP 55845 and (2) in young rats after a selective cholinergic denervation of the hippocampus by the immunotoxin 192 IgG-saporin. The results did not indicate statistically relevant age-related effects of CGP 55845. In contrast, the loss of the cholinergic innervation by the immunotoxin induced a significant increase in both the amplitude and duration of the NMDAr-mediated fEPSPs. Our results indicate that the functional properties of the ionotropic glutamate receptor subtypes located on CA1 pyramidal cells are differentially affected by aging and suggest that the cholinergic deficit that occurs during aging may be involved in the maintenance of robust NMDAr-mediated synaptic responses.
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PMID:Alteration of NMDA receptor-mediated synaptic responses in CA1 area of the aged rat hippocampus: contribution of GABAergic and cholinergic deficits. 988 20

Repetitive activation of corticostriatal fibers produces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of synaptic plasticity might be considered the possible neural basis of some forms of motor learning and memory. In the present study, intracellular recordings were performed from rat corticostriatal slice preparations to study the role of glutamate and other critical factors underlying striatal LTD. In current-clamp, but not in voltage-clamp experiments, brief focal applications of glutamate, as well as high-frequency stimulation (HFS) of corticostriatal fibers, induced LTD. This pharmacological LTD and the HFS-induced LTD were mutually occlusive, suggesting that both forms of synaptic plasticity share common induction mechanisms. Isolated activation of either non-NMDA-ionotropic glutamate receptors (iGluRs) or metabotropic glutamate receptors (mGluRs), respectively by AMPA and t-ACPD failed to produce significant long-term changes of corticostriatal synaptic transmission. Conversely, LTD was obtained after the simultaneous application of AMPA plus t-ACPD. Moreover, also quisqualate, a compound that activates both iGluRs and group I mGluRs, was able to induce this form of pharmacological LTD. Electrical depolarization of the recorded neurons either alone or in the presence of t-ACPD and dopamine (DA) failed to mimic the effects of the activation of glutamate receptors in inducing LTD. However, electrical depolarization was able to induce LTD when preceded by coadministration of t-ACPD, DA, and a low dose of hydroxylamine, a compound generating nitric oxide (NO) in the tissue. None of these compounds alone produced LTD. Glutamate-induced LTD, as well as the HFS-induced LTD, was blocked by L-sulpiride, a D2 DA receptor antagonist, and by 7-nitroindazole monosodium salt, a NO synthase inhibitor. The present study indicates that four main factors are required to induce corticostriatal LTD: (1) membrane depolarization of the postsynaptic neuron; (2) activation of mGluRs; (3) activation of DA receptors; and (4) release of NO from striatal interneurons.
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PMID:Glutamate-triggered events inducing corticostriatal long-term depression. 1040 46

Two different forms of synaptic plasticity have been found at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Striatal LTD and LTP are evoked following the repetitive stimulation of corticostriatal fibers and are dependent on the glutamate ionotropic receptor subtype activated. Recent experimental evidence indicates that two different subtypes of interneurons attend in the correct processing of information flow arising from the cortex and leading to striatal LTD or LTP. Acetylcholine (Ach) and nitric oxide (NO) producing striatal interneurons, in fact, are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exerts a feed-forward control of the excitability of striatal projection neurons ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse.
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PMID:Permissive role of interneurons in corticostriatal synaptic plasticity. 1061 92

Ceramide, a sphingomyelin-derived second messenger, mediates cellular signals of cytokines such as tumor necrosis factor-alpha that are rapidly produced in the brain in response to vigorous neuronal activity and tissue injury. Using whole-cell patch-clamp recordings, the present study examined whether ceramide modulated excitatory postsynaptic currents mediated by ionotropic glutamate receptors in CA1 pyramidal neurons of rat hippocampal slices. Application of N-acetyl-D-sphingosine, a synthetic cell-permeable ceramide analog, promptly produced a slight increase of excitatory postsynaptic current amplitude lasting for about 3 min. However, this transient enhancement was followed by a profoundly delayed-onset, sustained depression of synaptic excitatory postsynaptic currents in a concentration-dependent fashion (1-30 microM). This ceramide-induced sustained depression was not associated with changes in paired-pulse facilitation, a phenomenon resulting from an alteration of presynaptic transmitter release. Dihydro-N-acetyl-D-erythro-sphingosine (10 microM), an inactive analog of N-acetyl-D-sphingosine, did not affect synaptic excitatory postsynaptic currents, indicating the specificity of N-acetyl-D-sphingosine's action. The induction of ceramide-induced sustained depression was primarily dependent on the activation of postsynaptic protein phosphatases, being considerably blocked by loading 30 nM okadaic acid (a potent inhibitor of protein phosphatases 1 and 2A) into neurons. In addition, following a stable establishment of ceramide-induced sustained depression, a protocol for inducing long-term depression caused no additional decreases in excitatory postsynaptic current amplitude, and vice versa. The study suggests that ceramide induces a long-term depressed modulation on synaptic transmission mediated by ionotropic glutamate receptors in the hippocampus, possibly through the activation of postsynaptic protein phosphatases 1 and 2A. In addition, ceramide-induced sustained depression seems to share some common mechanisms with long-term depression, such as the cascades of events resulting from the activation of protein phosphatases. Collectively, the long-term depressed modulation of ceramide on ionotropic glutamate receptor-mediated functions may be particularly important in various physiological and/or pathological conditions, in which the ceramide signaling pathway is activated in the mammalian brain.
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PMID:Ceramide-induced sustained depression of synaptic currents mediated by ionotropic glutamate receptors in the hippocampus: an essential role of postsynaptic protein phosphatases. 1068 65

Glutamic acid is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Specific receptors bind glutamate and some of these when activated open an integral ion channel and are thus known as ionotropic receptors. Within the ionotropic family of glutamate receptors, three major subtypes have been identified using classical specific agonist activation, selective competitive antagonists together with their structural heterogeneity. These receptors have thus been named N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate receptors. The NMDA receptor has sites in addition to its agonist-binding site and these seem to either positively or negatively modulate the agonist effect. The NMDA receptor also is unique in that another amino acid, glycine, acts as a co-agonist with glutamate. Changes in glutamate transmission have been associated with a number of CNS pathologies; these include, acute stroke, chronic neurodegeneration, chronic pain, depression, drug dependency, epilepsy, Parkinson's Disease and schizophrenia.
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PMID:Excitatory amino acid agonists and antagonists: pharmacology and therapeutic applications. 1081 62

Neurodegeneration in Lurcher (Lc) mice results from constitutive activation of delta 2, a subunit of ionotropic glutamate receptors (GluRs) with unknown natural ligands and channel properties. Homo-oligomeric channels of GluR-delta2 with the Lurcher mutation (GluR-delta 2(Lc)) expressed in human embryonic kidney 293 cells showed a doubly rectifying current-voltage relation reminiscent of the block by intracellular polyamines in AMPA/kainate channels. Similarly, the fraction of the total current carried by Ca(2+) was approximately 2-3%, comparable with that found in Ca(2+)-permeable AMPA/kainate channels. Currents through GluR-delta 2(Lc) channels were also potentiated by extracellular Ca(2+) in a biphasic manner, with maximal potentiation occurring at physiological concentrations of Ca(2+). We examined the functional role of the Q/R site in GluR-delta 2(Lc) by replacing glutamine with arginine. Analogous to AMPA/kainate receptors, GluR-delta 2(Lc)(R) channels showed no voltage-dependent block by intracellular polyamines and were nominally impermeable to Ca(2+). The potentiation by Ca(2+), however, remained intact. Hence, GluR-delta 2(Lc) channels are functionally similar to the AMPA/kainate receptor channels, consistent with the high-sequence identity shared by these subunits within the channel-lining M2 and M3 segments. Furthermore, potentiation by Ca(2+) and a permeability to Ca(2+) comparable with that of AMPA/kainate receptors provide a possible cause for cell death in Lurcher mice and may contribute to cerebellar long-term depression under physiological conditions.
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PMID:The Lurcher mutation identifies delta 2 as an AMPA/kainate receptor-like channel that is potentiated by Ca(2+). 1093 45


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