Neuroscience
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In this study, we assessed the effects of varying tetanus and test-pulse intensity on the magnitude of long-term potentiation (LTP) in the perforant path-dentate gyrus projection of urethane-anaesthetized rats. We developed a novel within-subjects procedure in which test-pulse-stimulation intensity (60-1000 μA) was varied quasi-randomly under computer control throughout the recording period. After a baseline period, we applied a high-frequency tetanus, the intensity of which was varied over the same range as test-pulse intensity, but between subjects. ⋯ After 1000-μA tetanization of the original ('upstream') site, fEPSPs were again depressed in response to test stimulation of the upstream site, but only potentiation was observed in response to stimulation of the downstream site. This is consistent with the idea that the depression induced by intense tetanization results from local changes at the stimulation site. In conclusion, while tetanus intensity must exceed the LTP induction threshold, intensities above 500 μA should be avoided; in the present study, tetanization at 250-500 μA yielded maximal levels of LTP.
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Neuronal electrical activity has been known to affect the viability of neurons in the central nervous system. Here we show that long-lasting membrane depolarization induced by elevated extracellular K(+) recruits nitric oxide (NO)/soluble guanylyl cyclase/protein kinase G signaling pathway, induces 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP)-mediated protein S-guanylation, and confers dopaminergic neuroprotection. Treatment of primary mesencephalic cell cultures with 1-methyl-4-phenylpyridinium (MPP(+)) for 72 h decreased the number of dopaminergic neurons, whereas the cell loss was markedly inhibited by elevated extracellular concentration of K(+) (+40 mM). ⋯ Zinc protoporphyrin IX also inhibited the neuroprotective effect of elevated extracellular K(+). On the other hand, KT5823 or Rp-8-Br-PET-cGMPS did not inhibit the induction of HO-1 protein expression by 8-nitro-cGMP, although these protein kinase G inhibitors abrogated the neuroprotective effect of 8-nitro-cGMP. These results suggest that protein S-guanylation (leading to HO-1 induction) as well as canonical protein kinase G signaling pathway plays an important role in NO-mediated, activity-dependent dopaminergic neuroprotection.
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The serine protease subtilisin-A produces a long-term depression (LTD) of synaptic potentials in hippocampal slices which differs mechanistically from classical LTD. Since caspases have been implicated in hippocampal plasticity, this study examined a possible role for these enzymes in subtilisin-induced LTD. Subtilisin produced a concentration-dependent decrease in the size of field excitatory synaptic potentials (fEPSPs), which was not prevented or modified by the caspase inhibitors Z-VAD(OMe)-fmk and Z-DEVD-fmk. ⋯ Twin LTP stimulation generated a further increase in LTP amplitude in control slices but not in slices exposed to MG132. The results indicate that subtilisin does produce caspase activation but that this does not contribute to its induction of LTD. However, activation of the proteasome does contribute to subtilisin-induced LTD and may also play a modulatory role in electrically induced LTP.
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Parkinson's disease (PD) is the second most common neurodegenerative disorder manifesting in motor, cognitive and behavioral anomalies. Loss of dopaminergic neurons in the substantia nigra region of the brain is the hallmark feature of PD, which is attributed to oxidative and inflammatory stress besides other diverse factors and hence drugs targeting these pathways hold promise as neuro-therapeutics. The anti-oxidative as well as anti-inflammatory properties of sodium salicylate (SS), suggest its neuroprotective potentials in PD. ⋯ However, SS effectively abridged the levels of inflammatory mediators like cyclooxygenase-2 (COX-2), nuclear factor kappa B and inducible nitric oxide synthase. Correspondingly, a significant decrease in the levels of pro-inflammatory cytokines interleukin-6, interleukin-1β and tumor necrosis factor-α was also observed following SS co-treatment. Thus, neuroprotective efficacy of SS in this chronic model of PD can be largely attributed to its anti-inflammatory effects rather than its free radical-scavenging properties.
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Diffusion tensor imaging (DTI) provides information regarding white matter microstructure; however, macroscopic fiber architectures can affect DTI measures. A larger brain (fiber tract) has a 'relatively' smaller voxel size, and the voxels are less likely to contain more than one fiber orientation and more likely to have higher fractional anisotropy (FA). Previous DTI studies report left-to-right differences in the white matter; however, these may reflect true microscopic differences or be caused purely by volume differences. ⋯ Voxel-wise analysis with adjustment for volume asymmetry revealed many white matter FA asymmetries, including leftward asymmetry of the arcuate fasciculus and cingulum. The voxel-wise analysis showed a reduced number of regions with significant FA asymmetry compared with analysis performed without adjustment for volume asymmetry; however, the overall trend of the results was unchanged. The results of the present study suggest that these FA asymmetries are not caused by volume differences and reflect microscopic differences in the white matter.