A model of zinc dynamics evoked by intense stimulation at the cleft of hippocampal mossy fiber synapses.

Zinc is a transition metal that is particularly abundant in the mossy fibers of the hippocampal CA3 area. Despite the large number of studies about the zinc role in mossy fibers, the action of zinc in synaptic mechanisms is only partly known. The use of computational models can be a useful tool for this study. In a previous work, a model was developed to evaluate zinc dynamics at the mossy fiber synaptic cleft, following weak stimulation, insufficient to evoke zinc entry into postsynaptic neurons. For intense stimulation, cleft zinc effluxes must be considered. Therefore, the initial model was extended to include postsynaptic zinc effluxes based on the Goldman-Hodgkin-Katz current equation combined with Hodgkin and Huxley conductance changes. These effluxes occur through different postsynaptic escape routes, namely L- and N-types voltage-dependent calcium channels and NMDA receptors. For that purpose, various stimulations were assumed to induce high concentrations of cleft free zinc, named as intense (10 µM), very intense (100 µM) and extreme (500 µM). It was observed that the main postsynaptic escape routes of cleft zinc are the L-type calcium channels, followed by the NMDA receptor channels and by N-type calcium channels. However, their relative contribution for cleft zinc clearance was relatively small and decreased for higher amounts of zinc, most likely due to the blockade action of zinc in postsynaptic receptors and channels. Therefore, it can be concluded that the larger the zinc release, the more predominant the zinc uptake process will be in the cleft zinc clearance.

Effect of tolbutamide on tetraethylammonium-induced postsynaptic zinc signals at hippocampal mossy fiber-CA3 synapses.

The application of tetraethylammonium (TEA), a blocker of voltage-dependent potassium channels, can induce long-term potentiation (LTP) in the synaptic systems CA3-CA1 and mossy fiber-CA3 pyramidal cells of the hippocampus. In the mossy fibers, the depolarization evoked by extracellular TEA induces a large amount of glutamate and also of zinc release. It is considered that zinc has a neuromodulatory role at the mossy fiber synapses, which can, at least in part, be due to the activation of presynaptic ATP-dependent potassium (KATP) channels. The aim of this work was to study properties of TEA-induced zinc signals, detected at the mossy fiber region, using the permeant form of the zinc indicator Newport Green. The application of TEA caused a depression of those signals that was partially blocked by the KATP channel inhibitor tolbutamide. After the removal of TEA, the signals usually increased to a level above baseline. These results are in agreement with the idea that intense zinc release during strong synaptic events triggers a negative feedback action. The zinc depression, caused by the LTP-evoking chemical stimulation, turns into potentiation after TEA washout, suggesting the existence of a correspondence between the observed zinc potentiation and TEA-evoked mossy fiber LTP.

Postsynaptic zinc potentiation elicited by KCl depolarization at hippocampal mossy fiber synapses.

The hippocampal mossy fibers contain a substantial quantity of loosely-bound zinc in their glutamatergic presynaptic vesicles, which is released in synaptic transmission processes. Despite the large number of studies about this issue, the zinc changes related to short and long-term forms of potentiation are not totally understood. This work focus on zinc signals associated with chemically-induced mossy fiber synaptic plasticity, in particular on postsynaptic zinc signals evoked by KCl depolarization. The signals were detected using the medium affinity fluorescent zinc indicator Newport Green. The application of large concentrations of KCl, 20 mM and 60 mM, in the extracellular medium evoked zinc potentiations that decreased and remained stable after washout of the first and the second media, respectively. These short and long-lasting enhancements are considered to be due to zinc entry into postsynaptic neurons. We have also observed that following established zinc potentiation, another application of 60 mM KCl only elicited further enhancement when combined with external zinc. These facts support the idea that the KCl-evoked presynaptic depolarization causes higher zinc release leading to zinc influx into the postsynaptic region.

Stationarity of the inter-event power-law distributions.

A number of human activities exhibit a bursty pattern, namely periods of very high activity that are followed by rest periods. Records of these processes generate time series of events whose inter-event times follow a probability distribution that displays a fat tail. The grounds for such phenomenon are not yet clearly understood. In the present work we use the freely available Wikipedia's editing records to unravel some features of this phenomenon. We show that even though the probability to start editing is conditioned by the circadian 24 hour cycle, the conditional probability for the time interval between successive edits at a given time of the day is independent from the latter. We confirm our findings with the activity of posting on the social network Twitter. Our results suggest that there is an intrinsic humankind scheduling pattern: after overcoming the encumbrance of starting an activity, there is a robust distribution of new related actions, which does not depend on the time of day at which the activity started.

Localized redox relays as a privileged mode of cytoplasmic hydrogen peroxide signaling.

Hydrogen peroxide (H2O2) is a key signaling agent. Its best characterized signaling actions in mammalian cells involve the early oxidation of thiols in cytoplasmic phosphatases, kinases and transcription factors. However, these redox targets are orders of magnitude less H2O2-reactive and abundant than cytoplasmic peroxiredoxins. How can they be oxidized in a signaling time frame? Here we investigate this question using computational reaction-diffusion models of H2O2 signaling. The results show that at H2O2 supply rates commensurate with mitogenic signaling a H2O2 concentration gradient with a length scale of a few tenths of µm is established. Even near the supply sites H2O2 concentrations are far too low to oxidize typical targets in an early mitogenic signaling time frame. Furthermore, any inhibition of the peroxiredoxin or increase in H2O2 supply able to drastically increase the local H2O2 concentration would collapse the concentration gradient and/or cause an extensive oxidation of the peroxiredoxins I and II, inconsistent with experimental observations. In turn, the local concentrations of peroxiredoxin sulfenate and disulfide forms exceed those of H2O2 by several orders of magnitude. Redox targets reacting with these forms at rate constants much lower than that for, say, thioredoxin could be oxidized within seconds. Moreover, the spatial distribution of the concentrations of these peroxiredoxin forms allows them to reach targets within 1 µm from the H2O2 sites while maintaining signaling localized. The recruitment of peroxiredoxins to specific sites such as caveolae can dramatically increase the local concentrations of the sulfenic and disulfide forms, thus further helping these species to outcompete H2O2 for the oxidation of redox targets. Altogether, these results suggest that H2O2 signaling is mediated by localized redox relays whereby peroxiredoxins are oxidized to sulfenate and disulfide forms at H2O2 supply sites and these forms in turn oxidize the redox targets near these sites.