Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All synaptically-based neuropsychological theories of learning postulate that there are changes resulting from neural activity which are long-lasting and confined to specific sets of synapses. In the past decade a form of synaptic strengthening known as long-term potentiation (LTP) has been found which results from high-frequency neural activity and is of sufficient duration to model as a learning mechanism. Some early tests of the synaptic specificity of LTP in area CA1 of the hippocampus indicated that although LTP was specific to the tetanized pathway, in a converging untetanized pathway it was associated with depression of synaptic transmission lasting for at least 30 min. However, others have found that this heterosynaptic depression more usually decays within 5-15 min post-tetanus despite the maintenance of LTP in the tetanized pathway. Similarly, in the dentate gyrus (DG), LTP of either the lateral (LPP) or medial (MPP) components of the perforant path afferents has been associated with only short-lasting reciprocal heterosynaptic depression. Here, using more detailed measurement of stimulus intensity curves, we report that tetanization of either MPP or LPP reliably depresses synaptic transmission in the other pathway for at least 3 h. This heterosynaptic depression, considerably smaller than the usual magnitude of LTP, was obtained regardless of whether LTP had been produced in the tetanized homosynaptic pathway. Heterosynaptic long-term depression was not observed if the test pathway had been previously tetanized.
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PMID:Asymmetric relationships between homosynaptic long-term potentiation and heterosynaptic long-term depression. 663 40

In urethane-anesthetized rats, cortical regions which provide distal dendritic excitation of the dentate gyrus and CA1 of the dorsal hippocampus were studied using current source density analysis. Electrical stimulation of the lateral perforant path (LPP) in the lateral angular bundle, lateral entorhinal cortex (LEC), and amygdala-entorhinal transition (TR) resulted in a current sink in the outer molecular layer of the dentate gyrus accompanied by proximal sources; this sink-source pattern is distinctly different from the source-sink-source pattern evoked by medial perforant path stimulation. The progressive decrease of the sink latency following stimulation of the TR, LEC, and LPP (11.6, 7.8, and 3.6 ms, respectively, at the dorsal blade of the dentate gyrus) suggests a possible sequence of orthodromic activation of these structures. Stimulation of the LEC or TR (collectively termed cortical stimulation) differed from LPP (fiber) stimulation. A low threshold and small chronaxie were characteristic of fiber rather than cortical stimulation. In addition, cortical stimulation, possibly through excitation of intracortical circuits, evoked larger paired-pulse facilitation of the excitatory postsynaptic currents in dentate gyrus and more symmetric excitation of the dorsal and ventral blades of the dentate gyrus as compared to fiber stimulation. Stimulation of the perirhinal cortex (PRh) evoked a short-latency sink in the outer molecular layer of the dentate gyrus with no paired-pulse facilitation, similar to fiber stimulation. A distal dendritic CA1 sink was observed after LPP but not after PRh stimulation. An ibotenic acid injection that lesioned almost all the cells in the perirhinal cortex confirmed the hypothesis that PRh stimulation activated fibers of passage, perhaps in the rostral ventrolateral angular bundle. We conclude that the PRh does not provide a significant excitatory input to the DG or CA1. We have found distinct dendritic excitation of the dentate gyrus by the lateral versus medial perforant paths, and by fiber (LPP and MPP) versus cortical (LEC and TR) stimulation. We also emphasize that processing in the entorhinal cortex is important in the temporal shaping of the signals afferent to the hippocampus.
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PMID:Lateral entorhinal, perirhinal, and amygdala-entorhinal transition projections to hippocampal CA1 and dentate gyrus in the rat: a current source density study. 974 27

The medial septal area of conscious rats was stimulated through previously implanted electrodes at a frequency of 7.7 Hz for 20 min each day for 7 days to evoke rhythmic slow activity in CA1 at a similar frequency to spontaneous theta. Two weeks later in the anaesthetized rats the effects of a single subcutaneous injection of nicotine (0.4 mg x kg(-1)) on fEPSPs, evoked in the dentate gyrus by separate stimulation of the MPP and LPP, were studied and compared with those obtained in controls. Nicotine increased the firing of locus coeruleus neurones and the slope of the fEPSPs evoked by LPP stimulation, but not by MPP stimulation. Prior theta driving considerably increased the effect of nicotine on the responses evoked by stimulation of the MPP and abolished the nicotine-induced potentiation of the responses evoked by stimulation of the LPP. The results are attributed to theta driving increasing the amount of noradrenaline released by nicotine and to noradrenaline producing a beta-adrenoceptor long-lasting potentiation at the medial perforant path synapse and a long-lasting depression at the lateral perforant path synapse.
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PMID:Theta driving both inhibits and potentiates the effects of nicotine on dentate gyrus responses. 1675 34

The medial septal area of conscious rats was stimulated through previously implanted electrodes at a frequency of 7.7 Hz for 20 min each day for 7 days to evoke rhythmic slow activity in CA1 at a similar frequency to spontaneous theta. Two weeks later in the anaesthetized rats the effects of a single subcutaneous injection of nicotine (0.4 mg/kg) on fEPSPs, evoked in the dentate gyrus by separate stimulation of the MPP and LPP, were studied and compared with those obtained in controls. Nicotine increased the firing of locus coeruleus neurons and the slope of the fEPSPs evoked by LPP stimulation, but not by MPP stimulation. Prior theta driving considerably increased the effect of nicotine on the responses evoked by stimulation of the MPP and abolished the nicotine-induced potentiation of the responses evoked by stimulation of the LPP. The results are attributed to theta driving increasing the amount of noradrenaline released by nicotine and to noradrenaline producing a beta-adrenoceptor long-lasting potentiation at the medial perforant path synapse and a long-lasting depression at the lateral perforant path synapse.
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PMID:Theta driving both inhibits and potentiates the effects of nicotine on dentate gyrus responses. 1745 36

In keeping with previous observations in the CA1 and the somatosensory neocortex of the brain of rat, 20-min applications of 2-deoxy-D-glucose (2DG; 10 mM, replacing glucose) induced a long-term potentiation (LTP)-like enhancement of field excitatory synaptic potentials (fEPSPs) in the dentate region of hippocampal slices. The effects of 2DG were not identical at synapses of medial and lateral perforant paths (MPP and LPP). At MPP synapses, there was no post-2DG early depression of fEPSPs and the potentiation reached +78.6 +/- 5.7 % (+/- standard error of the mean) 40 min after the return to glucose. In the presence of 50 microM D-amino-phosphono valerate (APV; an N-methyl-D-aspartate [NMDA] receptor antagonist), a marked post-2DG depression appeared and the subsequent LTP was reduced to +34.7 +/- 2.8 % (for both 2DG- and APV-treatment P<0.001 by ANOVA-2W). At LPP synapses, even under control conditions, there was a sharp post-2DG depression followed by LTP (+62.2 +/- 5.7 %) and APV had little effect on either the post-2DG depression or LTP, reducing the latter by only 24 % [the 2DG treatment was very significant (P<0.001) but not the APV treatment]. Thus, 2DG evokes both NMDAR-dependent and -independent components of LTP in the perforant pathways. In view of these findings, the consumption of 2DG could have significant effects on synaptic plasticity and cognitive function.
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PMID:Two-deoxyglucose-induced long-term potentiation in slices of rat dentrate gyrus. 1772 7

Non-selective inhibition of histone deacetylases (HDACs), enzymes that remove acetyl groups from histone core proteins, enhances cognition and NMDAR-dependent long-term potentiation at hippocampal CA3-CA1 synapses. It is not known whether this is a general mechanism by which HDACs modulate plasticity at other hippocampal synapses. Furthermore, it has yet to be tested whether HDAC inhibition can reverse deficits in synaptic plasticity in disease models. Here, we investigated whether inhibition of HDACs, and specifically HDAC3, a class I HDAC isoform known to negatively regulate hippocampus-dependent learning and memory, enhances LTP at medial perforant path-dentate granule cell (MPP-DGC) synapses in wild-type and Fragile X (Fmr1-/y) mice, a model with known LTP deficits at this synapse. The non-selective HDAC inhibitor trichostatin A (TSA) significantly increased the magnitude of LTP at MPP-DGC synapses in wild-type mice, similar to reports at CA3-CA1 synapses. The enhancement of LTP was mimicked by selective HDAC3 inhibition, implicating a role for this isoform in the negative regulation of synaptic plasticity. However, HDAC3 inhibition was completely ineffective in reversing the deficit in LTP at MPP-DGC synapses in slices from Fmr1-/y mice, and in fact, HDAC3 inhibition was unable to induce any improvement whatsoever. These findings indicate that the enhancing effect of HDAC3 inhibition on LTP in wild-type mice requires FMRP, revealing a novel role for FMRP in hippocampal plasticity.
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PMID:Increased long-term potentiation at medial-perforant path-dentate granule cell synapses induced by selective inhibition of histone deacetylase 3 requires Fragile X mental retardation protein. 2495 40

3-O-demethylswertipunicoside (3-ODS) has been reported to protect dopaminergic neurons against neurotoxicity induced by 1-methyl-4-phenylpyridinium (MPP(+)) in PC12 cells. Here, we investigate the neuroprotective effects in vivo and antioxidant activities in vitro of 3-ODS. In the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease (PD), 3-ODS dose-dependently improved motor coordination (as shown by rotarod test), increased the contents of dopamine (DA) and its metabolites in the striatum, and increased the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN). In addition, 3-ODS also increased the spine density in hippocampal CA1 neurons. In antioxidant assays, 3-ODS showed a strong capacity in scavenging hydroxyl radical, superoxide anion and 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radical in a concentration-dependent manner. Taken together, we conclude that 3-ODS attenuates the PD-related motor deficits mainly through its neuroprotective effects, growth-promoting effects on spine density, and its antioxidant activities.
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PMID:Neuroprotective effects of 3-O-demethylswertipunicoside against MPTP-induced Parkinson's disease in vivo and its antioxidant properties in vitro. 2621 Jun 18

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson's disease-like symptoms following administration to mice, monkeys, and humans. A common view is that MPTP is metabolized to 1-methyl-4-phenylpyridinium ion (MPP(+)) to induce its neurodegenerative effects on dopaminergic neurons in the substantia nigra (SN). Moreover, the hippocampus contains dopaminergic fibers, which are projecting from the ventral tegmental area, SN and pars compacta and contain the whole machinery required for dopamine synthesis making them sensitive to MPTP and MPP(+). Here, we present data showing that acute bath-application of MPP(+) elicited a dose-dependent facilitation followed by a depression of synaptic transmission of hippocampal Schaffer collaterals-CA1 synapses in mice. The effects of MPP(+) were not mediated by D1/D5- and D2-like receptor activation. Inhibition of the dopamine transporters did not prevent but increased the depression of excitatory post-synaptic field potentials. In the search for a possible mechanism, we observed that MPP(+) reduced the appearance of polyspikes in population spikes recorded in str. pyramidale and increased the frequency of miniature inhibitory post-synaptic currents. The acute effect of MPP(+) on synaptic transmission was attenuated by co-application of a GABAA receptor antagonist. Taking these data together, we suggest that MPP(+) affects hippocampal synaptic transmission by enhancing some aspects of the hippocampal GABAergic system.
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PMID:The neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) alters hippocampal excitatory synaptic transmission by modulation of the GABAergic system. 2630 Jul 34

Neurotoxins are harmful to nervous system and cause either neuronal cell death or impairment of synaptic activity, which contributes to Parkinson's disease or other neuronal disorders. Hippocampal synaptic plasticity was proposed as a cellular model for memory processing. In this study, we reported a novel effect of neurotoxin, 1-methyl-4-phenylpyridinium (MPP+), on metabotropic glutamate receptor 1/5 agonist, 3,5-dihydroxyphenylglycine (DHPG)-induced hippocampal synaptic plasticity, and MPP+ incubation blocked DHPG-induced hippocampal long-term depression (LTD) in Schaffer collateral-CA1 synapses. Our further findings indicated that, this blockage was reversed by pre-application of calpain inhibitor III, but not by cathepsin inhibitors. Biochemical analysis showed that MPP+ treatment stimulated calpain activation, displayed by spectrin breakdown. Interestingly, the level and activity of protein tyrosine phosphatase 1B (PTP1B) were reduced after MPP+ incubation and the decrease of PTP1B was prohibited by calpain inhibitor III. In addition, PTP1B inhibitor also blocked DHPG-induced LTD, mimicking the effect of MPP+. In summary, our data implicated that MPP+ activated calpain-dependent PTP1B degradation, which subsequently impaired hippocampal LTD. This novel effect of MPP+ might partially explain the impairment of memory processing in the pathogenesis of PD.
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PMID:MPP+ inhibits mGluR1/5-mediated long-term depression in mouse hippocampus by calpain activation. 2790 90

Inhibition of nerve growth and plasticity in the CNS is to a large part mediated by Nogo-like signaling, now encompassing a plethora of ligands, receptors, co-receptors and modulators. Here we describe the distribution and levels of mRNA encoding 11 key genes involved in Nogo-like signaling (Nogo-A, Oligodendrocyte-Myelin glycoprotein (OMgp), Nogo receptor 1 (NgR1), NgR2, NgR3, Lingo-1, TNF receptor orphan Y (Troy), Olfactomedin, Lateral olfactory tract usher substance (Lotus) and membrane-type matrix metalloproteinase-3 (MT3-MPP)), as well as BDNF and GAPDH. Expression was analyzed in nine different brain areas before, and at eight time points during the first 3 days after a strong neuroexcitatory stimulation, caused by one kainic acid injection. A temporo-spatial pattern of orderly transcriptional regulations emerges that strengthens the role of Nogo-signaling mechanisms for synaptic plasticity in synchrony with transcriptional increases of BDNF mRNA. For most Nogo-type signaling genes, the largest alterations of mRNA levels occur in the dentate gyrus, with marked alterations also in the CA1 region. Changes occurred somewhat later in several areas of the cerebral cortex. The detailed spatio-temporal pattern of mRNA presence and kainic acid-induced transcriptional response is gene-specific. We reveal that several different gene alterations combine to decrease (and later increase) Nogo-like signaling, as expected to allow structural plasticity responses. Other genes are altered in the opposite direction, suggesting that the system prepares in advance in order to rapidly restore balance. However, the fact that Lingo-1 shows a seemingly opposite, plasticity inhibiting response to kainic acid (strong increase of mRNA in the dentate gyrus), may instead suggest a plasticity-enhancing intracellular function of this presumed NgR1 co-receptor.
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PMID:Spatiotemporal and Long Lasting Modulation of 11 Key Nogo Signaling Genes in Response to Strong Neuroexcitation. 2844 90


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