Plasticity-dependent, full detonation at hippocampal mossy fiber–CA3 pyramidal neuron synapses

Mossy fiber synapses on CA3 pyramidal cells are 'conditional detonators' that reliably discharge postsynaptic targets. The 'conditional' nature implies that burst activity in dentate gyrus granule cells is required for detonation. Whether single unitary excitatory postsynaptic potentials (EPSPs) trigger spikes in CA3 neurons remains unknown. Mossy fiber synapses exhibit both pronounced short-term facilitation and uniquely large post-tetanic potentiation (PTP). We tested whether PTP could convert mossy fiber synapses from subdetonator into detonator mode, using a recently developed method to selectively and noninvasively stimulate individual presynaptic terminals in rat brain slices. Unitary EPSPs failed to initiate a spike in CA3 neurons under control conditions, but reliably discharged them after induction of presynaptic short-term plasticity. Remarkably, PTP switched mossy fiber synapses into full detonators for tens of seconds. Plasticity-dependent detonation may be critical for efficient coding, storage, and recall of information in the granule cell–CA3 cell network

Estimation of The Relationship Between The Travel Time of Flood Peaks and Peak Discharge on The Poprad River by Multilinear Flood Routing

The empirical relationship between travel-time of flood peaks and peak discharge was studied on a reach of the Poprad River in Slovakia. The data were fitted by regression and compared with the expected shapes as described in the literature. Further a chain of linear segments has been considered as the model of that relation. The number of segments parameters and the angles between theses in this piecewise linear model were fitted by optimisation of a conceptual multilinear flood routing model performance on a large flood wave with the help of a genetic algorithm. In the setup of the multilinear model the travel-time parameter of the model was allowed to vary with discharge according to the piecewise linear model of the travel time of flood peaks. The discrete state space representation of the Kalinin-Miljukov model was used as the basis for a multilinear discrete cascade flood routing model. The resulting relationship was compared with empirical data on travel times and used to model the variability of the time parameter in the discrete state space representation of the Kalinin and Miljukov model on three verification floods. The modelling results showed that the inclusion of empirical information on the variability of the travel-time with discharge even from one flood enables satisfactory accuracy for the prediction of the flood propagation process

Fast Inhibition of Glutamate-Activated Currents by Caffeine

Background: Caffeine stimulates calcium-induced calcium release (CICR) in many cell types. In neurons, caffeine stimulates CICR presynaptically and thus modulates neurotransmitter release. Methodology/Principal Findings: Using the whole-cell patch-clamp technique we found that caffeine (20 mM) reversibly increased the frequency and decreased the amplitude of miniature excitatory postsynaptic currents (mEPSCs) in neocortical neurons. The increase in mEPSC frequency is consistent with a presynaptic mechanism. Caffeine also reduced exogenously applied glutamate-activated currents, confirming a separate postsynaptic action. This inhibition developed in tens of milliseconds, consistent with block of channel currents. Caffeine (20 mM) did not reduce currents activated by exogenous NMDA, indicating that caffeine block is specific to non-NMDA type glutamate receptors. Conclusions/Significance: Caffeine-induced inhibition of mEPSC amplitude occurs through postsynaptic block of non-NMDA type ionotropic glutamate receptors. Caffeine thus has both pre and postsynaptic sites of action at excitatory synapses

"Der Balkan" in der Krone: Austria between "frontier Orientalism" and amnesiac nationalism

This article traces the “silent inscription” of (former) colonial relations in the European integration project to their re-inflection in an EU-sceptical medium. To do so, this contribution draws on a corpus of data comprising news-coverage, commentaries and readers’ letters published in Austria’s largest newspaper, the Kronen Zeitung, whose reach, influence and leanings are well-known. The analysis considers the Krone’s representations of, and discursive references to, “the Balkans” during the crises-littered period between 2009 and 2017. For analytical purposes this discussion focuses on a sub-sample of invocations of “the Balkans” in the Krone, which have appeared with growing frequency since 2015. Conceptually, the discourse-analytical notion of the topos, or argumentative structure, and anthropological literature on “identity grammars” inform the analysis. The discussion reveals continuities with Austria’s historically long-established representational regimes of South-Eastern Europe, and novel discursive features. A contemporary paternalism is shown to re-appropriate the nineteenth-century topos of Austria’s alleged “civilizing mission” and what André Gingrich (2005) has described as Central Europe’s “frontier Orientalism”. Further, preoccupations with “the Balkan-route” and its closure articulate a topos of external threats tied to recent migration flows. The article reflects on an “amnesiac nationalism”, and its post-imperial entanglements, that are currently re-shaping the European Union

Presynaptic External Calcium Signaling Involves the Calcium-Sensing Receptor in Neocortical Nerve Terminals

Nerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca(2+)] ([Ca(2+)](o)) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca(2+)](o) sensor. Here, we identify the first component in a presynaptic calcium signaling pathway.By combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca(2+)](o) than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents.Our experiments identify CaSR as the first component in the [Ca(2+)](o) sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca(2+)](o) will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca(2+)](o) following its entry via voltage-activated Ca(2+) channels. CaSR may detects such falls in [Ca(2+)](o) and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca(2+)](o) on release probability. CaSR is positioned to detect the dynamic changes of [Ca(2+)](o) and provide presynaptic feedback that will alter brain excitability

Suppression of Ribosomal Function Triggers Innate Immune Signaling through Activation of the NLRP3 Inflammasome

Some inflammatory stimuli trigger activation of the NLRP3 inflammasome by inducing efflux of cellular potassium. Loss of cellular potassium is known to potently suppress protein synthesis, leading us to test whether the inhibition of protein synthesis itself serves as an activating signal for the NLRP3 inflammasome. Murine bone marrow-derived macrophages, either primed by LPS or unprimed, were exposed to a panel of inhibitors of ribosomal function: ricin, cycloheximide, puromycin, pactamycin, and anisomycin. Macrophages were also exposed to nigericin, ATP, monosodium urate (MSU), and poly I:C. Synthesis of pro-IL-ß and release of IL-1ß from cells in response to these agents was detected by immunoblotting and ELISA. Release of intracellular potassium was measured by mass spectrometry. Inhibition of translation by each of the tested translation inhibitors led to processing of IL-1ß, which was released from cells. Processing and release of IL-1ß was reduced or absent from cells deficient in NLRP3, ASC, or caspase-1, demonstrating the role of the NLRP3 inflammasome. Despite the inability of these inhibitors to trigger efflux of intracellular potassium, the addition of high extracellular potassium suppressed activation of the NLRP3 inflammasome. MSU and double-stranded RNA, which are known to activate the NLRP3 inflammasome, also substantially inhibited protein translation, supporting a close association between inhibition of translation and inflammasome activation. These data demonstrate that translational inhibition itself constitutes a heretofore-unrecognized mechanism underlying IL-1ß dependent inflammatory signaling and that other physical, chemical, or pathogen-associated agents that impair translation may lead to IL-1ß-dependent inflammation through activation of the NLRP3 inflammasome. For agents that inhibit translation through decreased cellular potassium, the application of high extracellular potassium restores protein translation and suppresses activation of the NLRP inflammasome. For agents that inhibit translation through mechanisms that do not involve loss of potassium, high extracellular potassium suppresses IL-1ß processing through a mechanism that remains undefined

Social Transfer of Pathogenic Fungus Promotes Active Immunisation in Ant Colonies

Social contact with fungus-exposed ants leads to pathogen transfer to healthy nest-mates, causing low-level infections. These micro-infections promote pathogen-specific immune gene expression and protective immunization of nest-mates

Loose coupling between Ca^2+ channels and release sensors at a plastic hippocampal synapse

The distance between Ca^2+ channels and release sensors determines the speed and efficacy of synaptic transmission. Tight "nanodomain" channel-sensor coupling initiates transmitter release at synapses in the mature brain, whereas loose "microdomain" coupling appears restricted to early developmental stages. To probe the coupling configuration at a plastic synapse in the mature central nervous system, we performed paired recordings between mossy fiber terminals and CA3 pyramidal neurons in rat hippocampus. Millimolar concentrations of both the fast Ca^2+ chelator BAPTA [1,2-bis(2-aminophenoxy)ethane- N,N, N′,N′-tetraacetic acid] and the slow chelator EGTA efficiently suppressed transmitter release, indicating loose coupling between Ca^2+ channels and release sensors. Loose coupling enabled the control of initial release probability by fast endogenous Ca^2+ buffers and the generation of facilitation by buffer saturation. Thus, loose coupling provides the molecular framework for presynaptic plasticity

Caffeine does not inhibit postsynaptic NMDA-receptor mediated currents (I_NMDA).

<p>(A) NMDA (20 µM) was applied to neurons in whole-cell voltage clamp in the presence of glycine and TTX, and zero extracellular Mg²⁺. Individual traces from a representative recording of I_NMDA before (black), during (blue) and after (red) the addition of 20 mM caffeine. (B) Average peak I_NMDA for single applications of NMDA before, during, and after 20 mM caffeine application (120 second interval).</p

Caffeine reversibly decreases mEPSC amplitude.

<p>(A) Recording of mEPSCs in whole-cell voltage-clamp in the presence of TTX (1 µM). Caffeine (20 mM) caused a clear reversible decrease in mEPSC size. The fast rise and exponential fall of synaptic currents was clear throughout recording (insets). (B) Amplitude histograms of events in A 200 seconds immediately before caffeine (black) and during the last 200 seconds of caffeine application (blue). (C) Average mEPSC amplitudes for seven cells before (black), during (blue), and after (red) caffeine application. (D) Normalized average diary plots of mEPSC frequency (top) and amplitude (bottom), n = 7. Bin size = 10 seconds. Each point is normalized to the average of 200 seconds of data recorded before drug application.</p