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)

Release of GABA from the terminals of hippocampal inhibitory neurons is inhibited by activation of GABAB autoreceptors and mu opioid receptors. However, it is not known whether these presynaptic processes affect all inhibitory synapses equally. We examined the effects of the GABAB receptor agonist baclofen and the mu opioid receptor agonist DAGO on postsynaptic currents evoked by minimal stimulation of inhibitory fibers (meIPSCs) in area CA3. Baclofen reversibly depressed approximately half of the meIPSCs evoked in the stratum pyramidale. The remaining meIPSCs were unaffected despite a coincident depression of spontaneous IPSCs. In contrast, all meIPSCs were depressed by DAGO. In addition, minimal stimulation in the stratum radiatum evoked meIPSCs that were always depressed by baclofen. These results indicate that regulation of GABA release by GABAB autoreceptors occurs at a subset of inhibitory synapses and that GABAB-resistant inhibitory synapses are located on pyramidal neuron somata. Hippocampal inhibitory neurons may be heterogeneous with respect to presynaptic receptor-mediated regulation of GABA release.
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PMID:Heterogeneity in presynaptic regulation of GABA release from hippocampal inhibitory neurons. 827 77

1. The electrophysiological action of the mu-opioid receptor-preferring agonist D-Ala2, MePhe4, Met(O)5-ol-enkephalin (FK 33-824) on synaptic transmission has been studied in area CA3 of organotypic rat hippocampal slice cultures. 2. FK 33-824 (1 microM) had no effect on the amplitude of pharmacologically isolated N-methyl-D-aspartate (NMDA) or non-NMDA receptor-mediated EPSPs. 3. FK 33-824 (10 nM to 10 microM) reduced the amplitude of monosynaptic inhibitory postsynaptic potentials (IPSPs) that were elicited in pyramidal cells with local stimulation after pharmacological blockade of excitatory amino acid receptors. This effect was reversible, dose-dependent, and sensitive to naloxone and the mu-receptor antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP). FK 33-824 at 1 microM caused a mean reduction in the amplitude of the monosynaptic IPSP of 70%. 4. Neither delta- nor kappa-receptor-preferring agonists had any effect on excitatory or inhibitory synaptic potentials. 5. The disinhibitory action of FK 33-824 was blocked by incubating the cultures with pertussis toxin (500 ng/ml for 48 h) or by stimulation of protein kinase C with phorbol 12,13-dibutyrate (PDBu, 0.5 microM). 6. The depression of monosynaptic IPSPs by FK 33-824 was unaffected by extracellular application of the K+ channel blockers Ba2+ or Cs+ (1 mM each). 7. FK 33-824 produced a decrease in the frequency of miniature, action potential-independent, spontaneous inhibitory synaptic currents (mIPSCs) recorded with whole-cell voltage-clamp techniques, but did not change their mean amplitude. Application of the Ca2+ channel blocker Cd2+ (100 microM) or of nominally Ca(2+)-free solutions did not alter either the frequency and amplitude of mIPSCs or the reduction of mIPSC frequency induced by FK 33-824. 8. The effect of FK 33-824 on spontaneous mIPSCs was prevented by naloxone, and by incubation of cultures with pertussis toxin. 9. These results indicate that mu-opioid receptors decrease GABA release presynaptically by a G protein-mediated inhibition of the vesicular GABA release process, and not by changes in axon terminal K+ or Ca2+ conductances that are sensitive to extracellular Ba2+, Cs+ or Cd2+.
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PMID:Mechanism of mu-opioid receptor-mediated presynaptic inhibition in the rat hippocampus in vitro. 830 42

Fast synaptic transmission in the central nervous system can be modulated by neurotransmitters and second-messenger pathways. For example, transmission at glutamatergic synapses can be depressed by the metabotropic glutamate receptor, providing autoreceptor-mediated negative feedback. Metabotropic glutamate receptor inhibition of Ca2+ channels may contribute to this pathway. In contrast, stimulation of protein kinase C can enhance excitatory synaptic transmission, whereas both depression and enhancement of Ca2+ current have been reported. Here we show that in hippocampal CA3 and cortical pyramidal neurons, activation of protein kinase C enhances current through N-type Ca2+ channels and, in addition, dramatically reduces G protein-dependent inhibition of these same channels by the metabotropic glutamate receptor. In parallel experiments on fast excitatory transmission at corticostriatal synapses, kinase C activators were similarly found to reduce the inhibitory effect produced by stimulation of the metabotropic glutamate receptor. The results show that second-to-second control of Ca2+ channels by the metabotropic glutamate receptor can itself be modulated on a slower timescale by protein kinase C. These mechanisms may be used in the control of fast excitatory synaptic transmission.
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PMID:Protein kinase C modulates glutamate receptor inhibition of Ca2+ channels and synaptic transmission. 838 Jun 26

The role of GABAb receptor activation in the expression of both interictal and ictal phenomena was investigated in slices of area CA3 of the rat hippocampal formation. Interictal-like bursts occurred following application of high frequency trains to the Schaffer collaterals. When two bursts were triggered using paired stimuli, profound depression of the second burst was seen 150-600 ms following the first burst. GABAb receptor antagonists potently reversed the paired pulse depression of the interictal-like bursts. Reversal of the paired depression was also accomplished by increasing the extracellular concentration of K+ by 2-3 mM. Additional experiments were performed in area CA3 to determine the role of GABAb receptor activation on the expression of ictal phenomena. Electrographic seizures (EGSs) were induced by application of high frequency trains. 2-Hydroxy-saclofen (200 microM) significantly decreased the duration of trains required to elicit EGSs. Taken together, these data suggest that GABAb receptor activation has potent inhibitory effects on both ictal and interictal-like events.
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PMID:Antiepileptic effects of GABAb receptor activation in area CA3 of rat hippocampus. 838 98

Protein synthesis, measured as [14C]-leucine incorporation into proteins, was studied in the normothermic rat brain following 15 min of transient cerebral ischaemia and 1 h, 24 h and 48 h of recirculation, and in the hypothermic (33 degrees C) brain following 1 h and 48 h of recirculation. Ischaemia was induced by bilateral common carotid occlusion combined with hypotension. Following normothermic ischaemia, incorporation of [14C]-leucine was depressed by 40-80% at 1 h of recirculation in all brain regions studied. At 48 h postischaemia, incorporation returned to normal or above normal levels in the inner layers of neocortex, the CA3 region, the striatum and the dentate gyrus, while in the outer layers of neocortex and in the hippocampal CA1 region the incorporation was persistently decreased by 26% and 40% respectively. At 24 and 48 h postischaemia, protein synthesis in the CA1 region and the striatum could be attributed to proliferating microglia. Intra-ischaemic hypothermia ameliorated the persistent depression of protein synthesis in the CA1 region at 48 h postischaemia, and a two-fold increase compared to the normothermic group was observed both in the CA1 region and the striatum. In the cortex, eucaryotic initiation factor 2 activity transiently decreased at 30 min postischaemia. In animals subjected to intra-ischaemic hypothermia, the eucaryotic initiation factor 2 activity was reduced by 50% of control at 30 min of recirculation compared with 77% in normothermic animals. We conclude that the postischaemic depression of protein synthesis is in part caused by a decrease in eucaryotic initiation factor 2 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Postischaemic changes in protein synthesis in the rat brain: effects of hypothermia. 840 56

Neuronal protein synthesis is severely depressed following stress such as heat-shock, hypoxia, and hypoglycemia. Following reversible cerebral ischemia, protein synthesis is transiently inhibited in ischemia-resistant areas, but persistently depressed in vulnerable brain regions. Eukaryotic initiation factor 2 (eIF-2) activity, that is, the formation of the ternary complex eIF-2.GTP.initiator 35S-Met-tRNA, a rate-limiting step in the initiation of cellular protein synthesis, was studied in the rat brain during and following 15 min of transient global cerebral ischemia. At 30 min and 1 hr of reperfusion, a general decrease of eIF-2 activity by approximately 50% was seen in the postmitochondrial supernatant (PMS). In the relatively resistant neocortex and CA3 region of the hippocampus, the eIF-2 activity returns to control levels at 6 hr of reperfusion, but remains depressed in the vulnerable striatum and the CA1 region. Similarly, the activity of the guanine nucleotide exchange factor (GEF), which catalyzes the exchange of GTP for GDP bound to eIF-2, a crucial step for the continued formation of the ternary complex, is transiently reduced in neocortex but persistently depressed in striatum. The postischemic decrease in eIF-2 activity is further attenuated by agarose-bound alkaline phosphatase, and mixing experiments revealed that a vanadate-sensitive phosphatase may be responsible for the depression. Addition of partially purified GEF to PMS from postischemic neocortex restored eIF-2 activity to control levels. We conclude that ischemia alters the balance between phosphorylation and dephosphorylation reactions, leading to an inhibition of GEF and a depression of ternary complex formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stress-induced inhibition of protein synthesis initiation: modulation of initiation factor 2 and guanine nucleotide exchange factor activities following transient cerebral ischemia in the rat. 847 77

Synapsin I and synapsin II are widely expressed synaptic vesicle phosphoproteins that have been proposed to play an important role in synaptic transmission and synaptic plasticity. To gain further insight into the functional significance of the phosphorylation sites on the synapsins, we have examined a number of synaptic processes thought to be mediated by protein kinases in knockout mice lacking both forms of synapsin (Rosahl et al., 1995). Long-term potentiation (LTP) at both the mossy fiber (MF)-CA3 pyramidal cell synapse and the Schaffer collateral-CA1 pyramidal cell synapse appears normal in hippocampal slices prepared from mice lacking synapsins. Moreover, the effects on synaptic transmission of forskolin at MF synapses and H-7 at synapses on CA1 cells are also normal in the mutant mice. These results indicate that the synapsins are not necessary for: (1) the induction or expression of two different forms of LTP in the hippocampus, (2) the enhancement in transmitter release elicited by activation of the cAMP-dependent protein kinase (PKA) and (3) the depression of synaptic transmission caused by H-7. Although disappointing, these results are important in that they exclude the most abundant family of synaptic phosphoproteins as an essential component of long-term synaptic plasticity.
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PMID:Long-term potentiation in mice lacking synapsins. 860 5

Long-term depression (LTD) was studied in hippocampal slices from neonatal rats at the synapse between CA3 and CA1 pyramidal neurons. The induction of LTD requires the pairing of Ca2+ influx into the postsynaptic CA1 neuron through voltage-gated calcium channels with activation of metabotropic glutamate receptors. The expression of this LTD is at least partly presynaptic, implying the need for a retrograde messenger. We present evidence that arachidonic acid might serve such a function. Thus, arachidonic acid applications simulate LTD whereas blockade of arachidonic acid release inhibits LTD.
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PMID:Hippocampal long-term depression: arachidonic acid as a potential retrograde messenger. 860 6

Long-term potentiation (LTP) and long-term depression (LTD) are activity-dependent changes in synaptic strength that may serve as the cellular mechanisms of information storage in the vertebrate brain. The mossy fibre-CA3 synapse displays NMDA (M-methyl-D-aspartate) receptor-independent forms of LTP and LTD that were thought to be non-associative. Here we report that the mossy fibre-CA3 synapse displays each of the known types of LTD in vivo, including associative, heterosynaptic and homosynaptic LTD. These types of LTD are induced when only two of the three conditions necessary for mossy fibre LTP induction are provided. Because some of these conditions can be provided by convergent CA3 afferents, each type of LTD can be induced in an associative manner, which suggests that LTD is involved in associative information storage. Similar to the induction of NMDA receptor-dependent LTD and LTP at other cortical synapses, mossy fibre LTD occurs when synaptic conditions are insufficient to induce LTP, and both LTP and LTD induction are influenced by previous synaptic activity, consistent with the view that common principles govern activity-dependent plasticity at cortical synapses.
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PMID:Associative, bidirectional modifications at the hippocampal mossy fibre-CA3 synapse. 863

To understand how the cerebellum adaptively times the classically conditioned nictitating membrane response (NMR), a model of the metabotropic glutamate receptor (mGluR) second messenger system in cerebellar Purkinje cells is constructed. In the model, slow responses, generated postsynaptically by mGluR-mediated phosphoinositide hydrolysis and calcium release from intracellular stores, bridge the interstimulus interval (ISI) between the onset of parallel fiber activity associated with the conditioned stimulus (CS) and climbing fiber activity associated with unconditioned stimulus (US) onset. Temporal correlation of metabotropic responses and climbing fiber signals produces persistent phosphorylation of both AMPA receptors and Ca(2+)-dependent K+ channels. This is responsible for long-term depression (LTD) of AMPA receptors. The phosphorylation of Ca(2+)-dependent K+ channels leads to a reduction in baseline membrane potential and a reduction of Purkinje cell population firing during the CS-US interval. The Purkinje cell firing decrease disinhibits cerebellar nuclear cells, which then produce an excitatory response corresponding to the learned movement. Purkinje cell learning times the response, whereas nuclear cell learning can calibrate it. The model reproduces key features of the conditioned rabbit NMR: Purkinje cell population response is timed properly; delay conditioning occurs for ISIs of up to 4 sec, whereas trace conditioning occurs only at shorter ISIs; mixed training at two different ISIs produces a double-peaked response; and ISIs of 200-400 msec produce maximal responding. Biochemical similarities between timed cerebellar learning and photoreceptor transduction, and circuit similarities between the timed cerebellar circuit and a timed dentate-CA3 hippocampal circuit, are noted.
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PMID:Metabotropic glutamate receptor activation in cerebellar Purkinje cells as substrate for adaptive timing of the classically conditioned eye-blink response. 864 19


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