UMLS:C0015672 - FACTA Search

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Query: UMLS:C0015672 (fatigue)
51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We tested a theoretical prediction that patterns of excitatory input activity that consistently fail to activate target neurons sufficiently to induce synaptic potentiation will instead cause a specific synaptic depression. To realize this situation experimentally, the Schaffer collateral projection to area CA1 in rat hippocampal slices was stimulated electrically at frequencies ranging from 0.5 to 50 Hz. Nine hundred pulses at 1-3 Hz consistently yielded a depression of the CA1 population excitatory postsynaptic potential that persisted without signs of recovery for greater than 1 hr after cessation of the conditioning stimulation. This long-term depression was specific to the conditioned input, ruling out generalized changes in postsynaptic responsiveness or excitability. Three lines of evidence suggest that this effect is accounted for by a modification of synaptic effectiveness rather than damage to or fatigue of the stimulated inputs. First, the effect was dependent on the stimulation frequency; 900 pulses at 10 Hz caused no lasting change, and at 50 Hz a synaptic potentiation was usually observed. Second, the depressed synapses continued to support long-term potentiation in response to a high-frequency tetanus. Third, the effects of conditioning stimulation could be prevented by application of NMDA receptor antagonists. Thus, our data suggest that synaptic depression can be triggered by prolonged NMDA receptor activation that is below the threshold for inducing synaptic potentiation. We propose that this mechanism is important for the modifications of hippocampal response properties that underlie some forms of learning and memory.
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PMID:Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. 135 90

In addition to the regulation of neuronal survival and differentiation, neurotrophins may play a role in synapse development and plasticity. Application of brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) in CA1 synapses of neonatal hippocampus, which otherwise exhibit only short-term potentiation. This is attributable, at least in part, to an attenuation of the synaptic fatigue induced by high-frequency stimulation (HFS). However, the prevention of synaptic fatigue by BDNF could be mediated by an attenuation of synaptic vesicle depletion from presynaptic terminals and/or a reduction of the desensitization of postsynaptic receptors. Here we provide evidence supporting a presynaptic effect of BDNF. The effect of BDNF on synaptic fatigue depended on the stimulation frequency, not on the stimulus duration nor on the number of stimulation pulses. BDNF was only effective when the synapses were stimulated at frequencies >50 Hz. Treatment with BDNF also potentiated paired-pulse facilitation (PPF), a parameter reflecting changes in the properties of presynaptic terminals. This effect of BDNF was restricted only to PPF elicited with interpulse intervals </=20 msec. Changes in the extracellular calcium concentration altered the magnitude of the BDNF effect on PPF and synaptic responses to HFS, suggesting that BDNF regulates neurotransmitter release. When the desensitization of glutamate receptors was blocked by cyclothiazide or aniracetam, the BDNF potentiation of the synaptic responses to HFS was unaltered. Taken together, these results suggest that BDNF acts presynaptically. When two pathways in the same slice were monitored simultaneously, BDNF treatment potentiated the tetanized pathway without affecting the synaptic efficacy of the untetanized pathway. The selective potentiation of high-frequency transmission by BDNF appears to contribute directly to the effect of BDNF on LTP rather than indirectly by inducing the release of additional diffusible factors. The preferential potentiation of highly active synapses by BDNF may have implications in the Hebbian mechanism of synaptic plasticity.
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PMID:Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. 971 54

Brain-derived neurotrophic factor (BDNF) promotes long-term potentiation (LTP) at hippocampal CA1 synapses by a presynaptic enhancement of synaptic transmission during high-frequency stimulation (HFS). Here we have investigated the mechanisms of BDNF action using two lines of BDNF knockout mice. Among other presynaptic impairments, the mutant mice exhibited more pronounced synaptic fatigue at CA1 synapses during high-frequency stimulation, compared with wild-type animals. Quantitative analysis of CA1 synapses revealed a significant reduction in the number of vesicles docked at presynaptic active zones in the mutant mice. Synaptosomes prepared from the mutant hippocampus exhibited a marked decrease in the levels of synaptophysin as well as synaptobrevin [vesicle-associated membrane protein (VAMP-2)], a protein known to be involved in vesicle docking and fusion. Treatment of the mutant slices with BDNF reversed the electrophysiological and biochemical deficits in the hippocampal synapses. Taken together, these results suggest a novel role for BDNF in the mobilization and/or docking of synaptic vesicles to presynaptic active zones.
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PMID:Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. 1036 30

Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-gamma (PLC-gamma) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-gamma. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-gamma, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.
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PMID:Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. 1049 6

Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded in area CA1 of rat hippocampal slices in vitro. The responses evoked by spontaneously released glutamate and GABA were recorded from area CA1 pyramidal neurons in rat hippocampal slices in whole-cell mode. The glutamate and GABA receptor-associated ligand-gated currents were obtained from dissociated single hippocampal pyramidal cells. The results showed that 4-aminopyridine (4-AP) had obvious effects on both presynaptic and postsynaptic events. Applications of 4-AP in micromolar concentration resulted in persistent enhancement of the initial slope of fEPSPs with the half-maximal enhancement concentration (EC(50)) of 46.7+/-2.68 microM. At the concentration of 200 microM, 4-AP increased the initial slopes of the total fEPSPs, NMDA- and AMPA-mediated fEPSPs components to 225.6+/-23.8%, 177.4+/-20.1% and 142.3+/-18.9%, respectively, but had no effect on the fiber volley. The half-maximal stimulus intensity to induce responses was reduced from 5.14+/-0.27 to 3.58+/-0.23 V. The frequencies of mEPSCs and mIPSCs were increased to 324.2+/-25.4% and 287.3+/-36.3% by 200 microM 4-AP. The amplitude histograms of mEPSCs and mIPSCs were fitted with Gaussian distributions. After 200 microM 4-AP application, the first and second peaks in Gaussian distributions of mEPSCs were shifted from 8.73+/-0.94 and 17.78+/-2.13pA to 10.48+/-0.82 and 21.14+/-2.45 pA, while those of mIPSCs were shifted from 13.65+/-0.96 and 25.51+/-2.95 pA to 11.21+/-1.04 and 23.08+/-2.37 pA. At 200 microM, 4-AP reduced paired-pulse facilitation and accelerated synaptic fatigue induced by stimulation at 10 Hz (for 1 s) and the ratio of fEPSPs(10)/fEPSPs(1) was decreased from 1.62+/-0.16 to 0.61+/-0.15. At 200 microM, 4-AP inhibited postsynaptic GABA currents induced by 5 microM GABA to 68.2+/-15.5%: by countering the effect of enhanced release of GABA from presynaptic terminals, this could depress the inhibitory pathway. Also at 200 microM, 4-AP increased NMDA currents to 155.3+/-17.8%, but had no significant effect on AMPA currents (94.2+/-15.6%). Our experimental results thus show that 4-AP-induced changes of synaptic transmission in area CA1 of rat hippocampus may be attributed to 4-AP's effects on both presynaptic terminals and postsynaptic receptors.
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PMID:Effect of 4-aminopyridine on synaptic transmission in rat hippocampal slices. 1505 26

In neurons, neurogranin (Ng) binds calmodulin (CaM), and its binding affinity is reduced by increasing Ca2+, phosphorylation by PKC, or oxidation by oxidants. Ng concentration in the hippocampus of adult mice varied broadly (Ng+/+, 160-370 and Ng+/-, approximately 70-230 pmol/mg); the level in Ng+/+ mice is one of the highest among all neuronal CaM-binding proteins. Among Ng+/- mice, but less apparent in Ng+/+, a significant relationship existed between their hippocampal levels of Ng and performances in the Morris water maze. Ng-/- mice performed poorly in this task; they also displayed deficits in high-frequency-induced long-term potentiation (LTP) in area CA1 of hippocampal slices, whereas low-frequency-induced long-term depression was enhanced. Thus, compared with Ng+/+ mice, the frequency-response curve of Ng-/- shifted to the right. Paired-pulse facilitation and synaptic fatigue during prolonged stimulation at 10 Hz (900 pulses) were unchanged in Ng-/- slices, indicating their normal presynaptic function. Measurements of Ca2+ transients in CA1 pyramidal neurons after weak and strong tetanic stimulations (100 Hz, 400 and 1000 msec, respectively) revealed a significantly greater intracellular Ca2+ ([Ca2+]i) response in Ng+/+ compared with Ng-/- mice, but the decay time constants did not differ. The diminished Ca2+ dynamics in Ng-/- mice are a likely cause of their decreased propensity to undergo LTP. Thus, Ng may promote a high [Ca2+]i by a "mass-action" mechanism; namely, the higher the Ng concentration, the more Ng-CaM complexes will be formed, which effectively raises [Ca2+]i at any given Ca2+ influx. This mechanism provides potent signal amplification in enhancing synaptic plasticity as well as learning and memory.
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PMID:Neurogranin/RC3 enhances long-term potentiation and learning by promoting calcium-mediated signaling. 1556 82

To search for potential mechanism that might alter synaptic transmission following Abeta increase we have examined the presynaptic component of transmitter release. As parameters of synaptic transmission that might underlie presynaptic mechanisms, we have used paired-pulse facilitation (PPF), post-tetanic potentiation (PTP), and synaptic fatigue (SF) at the connection between the hippocampal Schaffer-collateral pathway and CA1 pyramidal neurons in approximately 5 month old double transgenic mice overexpressing the mutated form of amyloid precursor protein (APPK670N, M671L) and presenilin 1 (PS1M146V). While the presynaptic mechanisms of PPF and PTP were not compromised in the APP/PS1 mice, SF was more pronounced in the double transgenic animals. The percentage of the 40th fEPSP slope over the first during the tetanus was 18 -/+ 3% in APP/PS1 vs. 26 -/+ 2% in WT. Thus, it is likely that presynaptic mechanisms underlying SF but not PPF and PTP, may account for synaptic dysfunction in APP/PS1 mice.
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PMID:Synaptic fatigue is more pronounced in the APP/PS1 transgenic mouse model of Alzheimer's disease. 1597 10

Cholestasis contributes to the genesis of fatigue through several mechanisms. Among these mechanisms, affected serotonergic neurotransmission is important in the pathogenesis of central fatigue. Previously, elevated levels of 5-hydroxyindole acetic acid (5-HIAA), the metabolite of 5-hydroxytryptamine (5-HT) and increased 5-HT(2) receptor density were demonstrated in the anterior hypothalamus and in the hippocampus of bile duct resected rats (BDR), respectively. The aim of this paper is to demonstrate evoked 5-HT release in selected brain regions like anterior hypothalamus and hippocampal CA1 regions of cholestatic rats using BDR rats as an experimental model for cholestasis. In this study, we analyzed the K+ evoked 5-HT and its metabolite 5-HIAA levels by using HPLC with electrochemical detection in the microdialysis samples collected from anterior hypothalamic and hippocampal CA1 regions of sham-operated and BDR rats (n = 6). The ratios of [5-HIAA] to [5-HT] following perfusion with 100 mM K+ artificial cerebrospinal fluid was used for the comparison of the evoked release of 5-HT. Locomotor activity was used to assess the signs of cholestasis associated fatigue in the BDR rats. The vertical and horizontal activity counts within 15 min were found to be decreased in the BDR rats compared to sham-operated rats (p < 0.05). Besides, the number of fecal boli (an index of emotionality) was also significantly fewer in the cholestatic rats (p < 0.05). No significant difference between the sham-operated and the BDR rats was detected in the basal 5-HT and 5-HIAA levels of anterior hypothalamus. K+ stimulation yielded a more profound increase in the [5-HIAA]/[5-HT] in the BDR rats (p < 0.05). The basal levels of 5-HT in CA1 region of the BDR rats was found to be lower than that of sham-operated group (p < 0.05), but no significant difference was observed in terms of evoked 5-HT release in both sham-operated and BDR rats. These findings imply the presence of affected serotonergic system in cholestasis.
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PMID:5-hydroxytryptamine release in the anterior hypothalamic and the hippocampal areas of cholestatic rats. 1618 17

Humans with an autosomal dominant missense mutation in fibroblast growth factor 14 (FGF14) have impaired cognitive abilities and slowly progressive spinocerebellar ataxia. To explore the mechanisms that may account for this phenotype, we show that synaptic transmission at hippocampal Schaffer collateral-CA1 synapses and short- and long-term potentiation are impaired in Fgf14-/- mice, indicating abnormalities in synaptic plasticity. Examination of CA1 synapses in Fgf14-/- mice show a significant reduction in the number of synaptic vesicles docked at presynaptic active zones and a significant synaptic fatigue/depression during high/low-frequency stimulation. In addition, mEPSC frequency, but not amplitude, is decreased in hippocampal neurons derived from Fgf14-/- mice. Furthermore, expression of selective synaptic proteins in Fgf14-/- mice was decreased. These findings suggest a novel role for FGF14 in regulating synaptic plasticity via presynaptic mechanisms by affecting the mobilization, trafficking, or docking of synaptic vesicles to presynaptic active zones.
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PMID:Impaired hippocampal synaptic transmission and plasticity in mice lacking fibroblast growth factor 14. 1720 50

Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms present in the eyes (CA I, II, IV and XII), with sulfonamides such as acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide, is still widely used for the systemic treatment of glaucoma. The mechanism of action of these drugs consists in inhibition of CA isozymes present in ciliary processes of the eye, with the consequent reduction of bicarbonate and aqueous humour secretion, and of elevated intraocular pressure (IOP) characteristic of this disease. As isoforms CA II/IV/XII are present in many other tissues/organs, generally, systemic CAIs possess undesired side effects such as numbness and tingling of extremities; metallic taste; depression; fatigue; malaise; weight loss; decreased libido; gastrointestinal irritation; metabolic acidosis; renal calculi and transient myopia. For avoiding these side effects, recently, topically effective CAIs have been developed in the last 10 years, with two drugs available clinically: dorzolamide and brinzolamide. Both these drugs are applied topically as water solutions/suspensions, alone or in combination with other agents (beta-blockers, prostaglandin derivatives, etc) and produce a consistent and prolonged reduction of IOP. Furthermore, recent reports show both the systemically as well as topically acting sulfonamide CAIs to be effective in the treatment of macular edema, macular degeneration disease, or diabetic retinopathy, for which pharmacological treatment is unavailable up to now. Much research is in act in the search of more effective topically acting CAIs, free of the inconveniences and side effects of the presently available drugs. For achieving this goal, two recently reported strategy, the tail approach and its variant, the sugar-tail approach, were extensively applied for the synthesis of large numbers of derivatives possessing desired physico-chemical properties. Many such new sulfonamides showed promising antiglaucoma activity in animal models of the disease.
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PMID:The development of topically acting carbonic anhydrase inhibitors as antiglaucoma agents. 1833 10

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