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)

Low-frequency stimulation of the Schaffer-commissural pathways in slices prepared from juvenile rats (postnatal day 10-15) results in a long-term depression (LTD) of synaptic transmission. 30 min after 5 min of stimulation at 5 Hz, the response to the stimulated pathway was decreased by 36%, whereas the response to an unstimulated pathway projecting to the same neuronal population was decreased by 20%. Stimulation in the presence of the NMDA receptor antagonist AP5 completely prevented homosynaptic LTD. The phospholipase A2 inhibitor, bromophenacylbromide, also significantly reduced the extent of LTD in both the stimulated and control pathways. LTD was accompanied by a decrease in paired-pulse facilitation, suggesting a change in transmitter release. It also resulted in an increased effect of iontophoretically applied perchlorate, an ion which increases both the affinity of glutamate for the synaptic alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionate (AMPA) receptors and synaptic responses, suggesting a change in postsynaptic receptors. These findings indicate that certain stimulation paradigms produce a combination of pre- and postsynaptic modifications that could underlie changes in synaptic efficacy.
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PMID:Blockade of long-term depression in neonatal hippocampal slices by a phospholipase A2 inhibitor. 791 48

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses occurs when these synapses are activated in conjunction with direct activation of voltage-gated calcium (Ca2+) channels of PCs. In the present study, we have used Aniracetam to test whether the expression of LTD at PF-PC synapses is due to a genuine modification of properties of alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptors of these neurons. Whole-cell recordings of PF-mediated EPSCs were performed in thin slices taken from 16-22-day-old rats. In all tested cells, bath application of Aniracetam potentiated PF-mediated EPSCs and prolonged their decay without notably changing their rising phase. On the other hand, Aniracetam prevented the induction of LTD by a pairing protocol with Ca2+ spikes and, conversely, the nootropic compound had a larger potentiating effect on PF-mediated EPSCs during expression of LTD than normally, when this change in synaptic efficacy had been induced prior to Aniracetam application. These data strongly suggest that LTD involves a desensitization of postsynaptic AMPA receptors at PF-PC synapses, or, at least, a change in their functional characteristics.
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PMID:Properties of glutamate receptors are modified during long-term depression in rat cerebellar Purkinje cells. 800 49

Glutamate-gated ion channels mediate most excitatory synaptic transmission in the central nervous system and play crucial roles in synaptic plasticity, neuronal development and some neuropathological conditions. These ionotropic glutamate receptors have been classified according to their preferred agonists as NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and KA (kainate) receptors. On the basis of sequence similarity and pharmacological properties, the recently cloned glutamate receptor subunits have been assigned as components of NMDA (NMDAR1, 2A-D), AMPA (GluR1-4) and KA (GluR5-7, KA1, KA2) receptors. Protein phosphorylation of glutamate receptors by protein kinase C and cyclic AMP-dependent protein kinase (PKA) has been suggested to regulate their function, possibly playing a prominent role in certain forms of synaptic plasticity such as long-term potentiation and long-term depression. Here we report that the GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. These results provide evidence that direct phosphorylation of glutamate receptors modulates their function.
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PMID:Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase. 809 92

Stimulation of carotid body chemoreceptors by saline saturated with 100% CO2 elicited an increase in mean arterial pressure, respiratory rate, tidal volume, and minute ventilation (VE). Microinjections of L-glutamate into a midline area 0.5-0.75 mm caudal and 0.3-0.5 mm deep with respect to the calamus scriptorius increased VE. Histological examination showed that the site was located in the commissural nucleus of the nucleus tractus solitarii (NTS). The presence of excitatory amino acid receptors [N-methyl-D-aspartic acid (NMDA); kainate, quisqualate/alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and trans 1-amino-cyclopentane-trans-1,3-dicarboxylic acid (ACPD)] in this area was demonstrated by microinjections of appropriate agonists. Simultaneous blockade of NMDA and non-NMDA receptors by combined injections of DL-2-aminophosphonoheptanoate (AP-7; 1 nmol) and 6,7-dinitro-quinoxaline-2,3-dione (DNQX; 1 nmol) abolished the responses to stimulation of carotid body on either side. Combined injections of AP-7 and DNQX did not produce a nonspecific depression of neurons because the responses to another agonist, carbachol, remained unaltered. Inhibition of the neurons in the aforementioned area with microinjections of muscimol (which hyperpolarizes neuronal cell bodies but not fibers of passage) also abolished the responses to subsequent carotid body stimulation on either side.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Excitatory amino acid receptors in commissural nucleus of the NTS mediate carotid chemoreceptor responses. 838 18

The distribution of glutamate receptors in the cerebellar cortex of the rhesus macaque was examined by light microscopic immunocytochemistry using an antibody specific to the N-methyl-D-aspartate (NMDA) R1 receptor subunit (i.e. NMDAR1) as well as antibodies specific to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits (i.e. GluR1, GluR2/3, and GluR4). NMDAR1 immunolabeling was most prevalent in the Purkinje cell perikarya and dendrities, but was also significant in the stellate and basket cells of the granular layer and Golgi cells of the molecular layer. On the other hand, GluRl and GluR4 immunolabeling was concentrated principally in the processes of the Bergmann glia located in the vicinity of the Purkinje cell perikarya. Although GluR2/3 immunolabeling also occurred in these Bergmann glia processes as well as in the Bergmann fibers, it was more pronounced in the Purkinje cell perikarya and dendrites; additionally, significant GluR2/3 labeling was evident in the stellate and basket cells of the molecular layer and medium-size soma of the granular layer (most likely Golgi cells). In situ hybridization histochemistry (ISHH), using cRNA probes to NMDAR1. GluR1.GluR2, and GluR3, showed glutamate receptor mRNA distribution patterns consistent with those disclosed in the immunocytochemical study. Furthermore, the ISHH findings suggest that the positive immunocytochemical labeling of Purkinje cells with the GluR2/3 antibody is most likely due to the gene expression of both GluR2 and GluR3 AMPA receptor subtypes. Taken together, the results are potentially important for the elucidation of mechanisms that control aspects of cerebellar function, such as long-term depression.
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PMID:Distribution of NMDA and AMPA receptors in the cerebellar cortex of rhesus macaques. 873 16

1. Using a rabbit cerebellar slice preparation, we stimulated a classical conditioning procedure by stimulating parallel fiber inputs to Purkinje cells with the use of a brief, high-frequency train of eight constant-current pulses 80 ms before climbing fiber inputs to the same Purkinje cell were stimulated with the use of a brief, lower frequency train of three constant-current pulses. In all experiments, we assessed the effects of stimulation by measuring the peak amplitude of Purkinje cell excitatory postsynaptic potentials (EPSPs) to single parallel fiber test pulses. 2. Intradendritically recorded Purkinje cell EPSPs underwent a long-term (> 20 min) reduction in peak amplitude (30%) after paired stimulation of the parallel and climbing fibers but not after unpaired or parallel fiber alone stimulation. We call this phenomenon pairing-specific long-term depression (PSD). 3. Facilitation of the peak amplitude of a second EPSP elicited by a parallel fiber train occurred both before and after paired stimulation suggesting that the locus of depression was not presynaptic. Depression of the peak amplitude of a depolarizing response to focal application of glutamate following pairings of parallel and climbing fiber stimulation added support to a suggested postsynaptic locus of the PSD effect. 4. The application of aniracetam potentiated EPSP peak amplitude by 40%, but these values returned to baseline as a result of pairings. With the removal of aniracetam from the bath 20 min after pairings, normal levels of pairing-specific EPSP depression were observed, indicating that the effect did not result from direct desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. 5. Incubation of slices in the protein kinase inhibitor H-7 potentiated EPSP peak amplitudes slightly (9%), but peak amplitudes returned to baseline levels after pairings. The net reduction in EPSP peak amplitude of < 10% after pairings suggested that H-7 partially blocked PSD and that, in turn, PSD involved protein kinases. 6. The means of induction and the specificity of those means suggest that the phenomenology of PSD is fundamentally different from that of long-term depression. PSD only occurs with pairings of trains of parallel fiber and climbing fiber stimulation; it occurs without the need for bicuculline; and it can overcome the blocking effects of aniracetam. 7. Nevertheless, the involvement of protein kinases and the potential role of calcium suggest that the mechanisms involved in the induction of PSD and long-term depression have a number of features in common. 8. Because of the pairing-specific nature of the long-term synaptic depression observed in these experiments, PSD provides a mechanism that may contribute to the role of the cerebellar cortex in classical conditioning.
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PMID:Pairing-specific long-term depression of Purkinje cell excitatory postsynaptic potentials results from a classical conditioning procedure in the rabbit cerebellar slice. 886 17

It has been shown recently that embryonic Purkinje cells grafted extraparenchymally into an intact cerebellum, in the absence of any sign of damage, are able to migrate into the host molecular layer where they receive a climbing fibre innervation. Using the same technique, we investigated the development of the electrophysiological properties of the synapses between the grafted cells and their main afferents. Purkinje cells either in the graft or having migrated into the molecular layer of the host were recorded using the whole-cell patch-clamp method in acutely prepared slices 17-112 days after grafting. Spontaneous postsynaptic currents with a single-exponential decay and mediated by GABAA receptors were very similar to those described in normal Purkinje cells. Excitatory postsynaptic currents (EPSCs) evoked by climbing fibre and by parallel fibre stimulation were blocked by an alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate antagonist, and displayed the linear current-voltage relation typical of postnatal Purkinje cells. The attainment of normal functional properties by the adult axons at the newly formed synaptic sites was shown by the expression of short-term facilitation of parallel fibre EPSCs and of short-term depression of climbing fibre EPSCs. The grafted Purkinje cells showed climbing fibre polyinnervation 17-20 days after grafting which evolved to monoinnervation at 23-45 days, confirming the completion of the developmental programme up to maturation. Our experiments support the view that the adult intact brain is able to accept and integrate an additional number of neurons which show fully mature electrophysiological properties which are electrophysiologically indistinguishable from those of the host neurons.
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PMID:Postsynaptic currents and short-term synaptic plasticity in Purkinje cells grafted onto an uninjured adult cerebellar cortex. 899 19

1. It is generally considered that glutamate-mediated transmission can be altered from a physiological to neurotoxic action when extracellular glutamate levels become excessive subsequent to impaired uptake and/or excessive release. However, high extracellular glutamate does not consistently correlate with neuronal dysfunction and death in vivo. The purpose of this study was to examine in situ the local depolarizations, as indicated by negative shifts of the extracellular field (d.c.) potential, produced by local inhibition of high-affinity glutamate uptake, with or without co-application of exogenous glutamate, in three brain regions of anaesthetized rats. 2. Microdialysis probes incorporating an electrode were used to apply exogenous glutamate and/or its uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC), and to monitor the resulting changes in extracellular glutamate and d.c. potential at the sites of application within the cortex, striatum and hippocampus. 3. Perfusion of 1 to 10 mM L-trans-PDC markedly and concentration-dependently increased extracellular glutamate levels (by up to 1700% of basal level in the parietal cortex). Despite their large magnitude, glutamate changes were associated with minor negative shifts of the d.c. potential (< 2 mV), which were not suppressed by the N-methyl-D-aspartate (NMDA)-channel blocker, dizocilpine (MK-801, 2 mg kg-1, i.v.), or the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/ kainate-receptor antagonist, 6-nitro-7-sulphamoylbenzo(f)quinoxaline-2,3-dione (NBQX, 30 mg kg-1, i.p.). L-trans-PDC had virtually identical concentration-dependent effects on dialysate glutamate in the hippocampus and striatum, but those induced in the cortex were around 40% larger (P < 0.002). In contrast, the associated depolarizations were around twice as large in the striatum and cortex as in the hippocampus (P < 0.002). Finally, co-application of L-trans-PDC did not enhance the d.c. potential changes evoked by perfusion of 5 or 20 mM glutamate. 4. As the neurotoxic potency of glutamate agonists is considered to be linked to excessive opening of glutamate-operated ion channels, these results challenge the notion that high extracellular glutamate levels may be the key to excitotoxicity in neurological disorders. In particular, they do not support the hypothesis that high extracellular glutamate causes the sudden negative shifts of the d.c. potential associated with ischaemia (i.e. anoxic depolarization), traumatic brain injury and spreading depression. Impaired uptake and excessive release of glutamate may well lead to excitotoxicity, but only at the synaptic level, not by spreading through the interstitial fluid.
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PMID:Effects of increased extracellular glutamate levels on the local field potential in the brain of anaesthetized rats. 931 49

The synaptic modifications underlying long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission in various brain structures may result from changes in the properties of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptors. In the present study, we report that treatment of rat synaptoneurosomes with increasing concentrations of phospholipase A2 (PLA2) produces a biphasic effect on AMPA receptor binding, with low concentrations causing a decrease and high concentrations an increase in agonist binding. Analysis of the saturation kinetics of 3H-AMPA binding revealed that the biphasic effect of PLA2 was due to modifications in receptor affinity and not to changes in the maximum number of binding sites for AMPA receptors. The 12-lipoxygenase inhibitors preferentially reduced PLA2-induced decrease in AMPA binding and treatment of hippocampal synaptoneurosomes with arachidonic acid (AA) or 12-HPETE, the first metabolite generated from the hydrolysis of AA by 12-lipoxygenases, decreased 3H-AMPA binding. Moreover, electrophysiological experiments indicated that the 12-lipoxygenase inhibitor baicalein totally blocked LTD formation in area CA1 of hippocampal slices. The decrease in 3H-AMPA binding elicited by low concentrations of PLA2, as well as the level of LTD, were partially reduced by AA-861, a 5-lipoxygenase inhibitor, while the cyclooxygenase inhibitor indomethacin did not prevent LTD formation or the effects of PLA2 on 3H-AMPA binding. Our results provide evidence for a possible involvement of lipoxygenase metabolites in the regulation of AMPA receptor during synaptic depression. In addition, they strongly support the idea that the same biochemical pathway, i.e., NMDA receptor activation and endogenous PLA2 stimulation, may represent a common mechanism resulting in AMPA receptor alterations for both LTP and LTD formation.
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PMID:Bidirectional modulation of AMPA receptor properties by exogenous phospholipase A2 in the hippocampus. 966 43

Kainate (KA) receptor activation depresses stimulus-evoked gamma-aminobutyric acid (GABA-mediated) synaptic transmission onto CA1 pyramidal cells of the hippocampus and simultaneously increases the frequency of spontaneous GABA release through an increase in interneuronal spiking. To determine whether these two effects are independent, we examined the mechanism by which KA receptor activation depresses the stimulus-evoked, inhibitory postsynaptic current (IPSC). Bath application of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)/KA receptor agonist KA in the presence of the AMPA receptor antagonist GYKI 53655 caused a large increase in spontaneous GABA release and a coincident depression of the evoked IPSC. The depressant action on the evoked IPSC was reduced, but not abolished, by the GABA(B) receptor antagonist SCH 50911, suggesting that the KA-induced increase in spontaneous GABA release depresses the evoked IPSC through activation of presynaptic GABA(B) receptors. KA had no resolvable effect on the potassium-induced increase in miniature IPSC frequency, suggesting that KA does not act through a direct effect on the release machinery or presynaptic calcium influx. KA caused a decrease in pyramidal cell input resistance, which was reduced by GABA(A) receptor antagonists. KA also caused a reduction in the size of responses to iontophoretically applied GABA, which was indistinguishable from the SCH 50911-resistant, residual depression of the evoked IPSC. These results suggest that KA receptor activation depresses the evoked IPSC indirectly by increasing interneuronal spiking and GABA release, leading to activation of presynaptic GABA(B) receptors, which depress GABA release, and postsynaptic GABA(A) receptors, which increase passive shunting.
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PMID:Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus. 1053 23


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