Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity.

GABA transporters control extracellular GABA, which regulates the key aspects of neuronal and network behaviour. A prevailing view is that modest neuronal depolarization results in GABA transporter type-1 (GAT-1) reversal causing non-vesicular GABA release into the extracellular space during intense network activity. This has important implications for GABA uptake-targeting therapies. Here we combined a realistic kinetic model of GAT-1 with experimental measurements of tonic GABAA receptor currents in ex vivo hippocampal slices to examine GAT-1 operation under varying network conditions. Our simulations predict that synaptic GABA release during network activity robustly prevents GAT-1 reversal. We test this in the 0 Mg(2+) model of epileptiform discharges using slices from healthy and chronically epileptic rats and find that epileptiform activity is associated with increased synaptic GABA release and is not accompanied by GAT-1 reversal. We conclude that sustained efflux of GABA through GAT-1 is unlikely to occur during physiological or pathological network activity

Estimating sampling biases and measurement uncertainties of AIRS/AMSU-A temperature and water vapor observations using MERRA reanalysis

We use MERRA (Modern Era Retrospective-Analysis for Research Applications) temperature and water vapor data to estimate the sampling biases of climatologies derived from the AIRS/AMSU-A (Atmospheric Infrared Sounder/Advanced Microwave Sounding Unit-A) suite of instruments. We separate the total sampling bias into temporal and instrumental components. The temporal component is caused by the AIRS/AMSU-A orbit and swath that are not able to sample all of time and space. The instrumental component is caused by scenes that prevent successful retrievals. The temporal sampling biases are generally smaller than the instrumental sampling biases except in regions with large diurnal variations, such as the boundary layer, where the temporal sampling biases of temperature can be ± 2 K and water vapor can be 10% wet. The instrumental sampling biases are the main contributor to the total sampling biases and are mainly caused by clouds. They are up to 2 K cold and > 30% dry over midlatitude storm tracks and tropical deep convective cloudy regions and up to 20% wet over stratus regions. However, other factors such as surface emissivity and temperature can also influence the instrumental sampling bias over deserts where the biases can be up to 1 K cold and 10% wet. Some instrumental sampling biases can vary seasonally and/or diurnally. We also estimate the combined measurement uncertainties of temperature and water vapor from AIRS/AMSU-A and MERRA by comparing similarly sampled climatologies from both data sets. The measurement differences are often larger than the sampling biases and have longitudinal variations

Central synapses release a resource-efficient amount of glutamate.

Why synapses release a certain amount of neurotransmitter is poorly understood. We combined patch-clamp electrophysiology with computer simulations to estimate how much glutamate is discharged at two distinct central synapses of the rat. We found that, regardless of some uncertainty over synaptic microenvironment, synapses generate the maximal current per released glutamate molecule while maximizing signal information content. Our result suggests that synapses operate on a principle of resource optimization

Volume-transmitted GABA waves pace epileptiform rhythms in the hippocampal network

Mechanisms that entrain and pace rhythmic epileptiform discharges remain debated. Traditionally, the quest to understand them has focused on interneuronal networks driven by synaptic GABAergic connections. However, synchronized interneuronal discharges could also trigger the transient elevations of extracellular GABA across the tissue volume, thus raising tonic conductance (Gtonic) of synaptic and extrasynaptic GABA receptors in multiple cells. Here, we monitor extracellular GABA in hippocampal slices using patch-clamp GABA "sniffer" and a novel optical GABA sensor, showing that periodic epileptiform discharges are preceded by transient, region-wide waves of extracellular GABA. Neural network simulations that incorporate volume-transmitted GABA signals point to a cycle of GABA-driven network inhibition and disinhibition underpinning this relationship. We test and validate this hypothesis using simultaneous patch-clamp recordings from multiple neurons and selective optogenetic stimulation of fast-spiking interneurons. Critically, reducing GABA uptake in order to decelerate extracellular GABA fluctuations-without affecting synaptic GABAergic transmission or resting GABA levels-slows down rhythmic activity. Our findings thus unveil a key role of extrasynaptic, volume-transmitted GABA in pacing regenerative rhythmic activity in brain networks

Electric Fields Due to Synaptic Currents Sharpen Excitatory Transmission

The synaptic response waveform, which determines signal integration properties in the brain, depends on the spatiotemporal profile of neurotransmitter in the synaptic cleft. Here, we show that electrophoretic interactions between AMPA-receptor-mediated excitatory currents and negatively charged glutamate molecules accelerate the clearance of glutamate from the synaptic cleft, speeding-up synaptic responses. This phenomenon is reversed upon depolarization and diminished when intra-cleft electric fields are weakened through a decrease in the AMPA receptor density. In contrast, the kinetics of receptor-mediated currents evoked by direct application of glutamate are voltage-independent, as are synaptic currents mediated by the electrically neutral neurotransmitter GABA. Voltage-dependent temporal tuning of excitatory synaptic responses may thus contribute to signal integration in neural circuits

Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

Improving Global Precipitation Product Access at the GES DISC

The NASA Goddard Earth Sciences Data and Information Services Center (GES DISC) has been actively and continually engaged in improving the access to and use of Global Precipitation Measurement (GPM), Tropical Precipitation Measuring Mission (TRMM), and other precipitation data, including the following new services and ongoing development activities: Updates on GPM products and data services; New features in Giovanni; Ongoing development activities; Precipitation product and service outreach activities

Improving Global Precipitation Product Access at the GES DISC

The NASA Goddard Earth Sciences Data and Information Services Center (GES DISC) has been actively and continually engaged in improving the access to and use of Global Precipitation Measurement (GPM), Tropical Precipitation Measuring Mission (TRMM), and other precipitation data, including the following new services and Ongoing development activities: Updates on GPM products and data services, New features in Giovanni, Ongoing development activities; and Precipitation product and service outreach activities

Stochastic models for the in silico simulation of synaptic processes

Background: Research in life sciences is benefiting from a large availability of formal description techniques and analysis methodologies. These allow both the phenomena investigated to be precisely modeled and virtual experiments to be performed in silico. Such experiments may result in easier, faster, and satisfying approximations of their in vitro/vivo counterparts. A promising approach is represented by the study of biological phenomena as a collection of interactive entities through process calculi equipped with stochastic semantics. These exploit formal grounds developed in the theory of concurrency in computer science, account for the not continuous, nor discrete, nature of many phenomena, enjoy nice compositional properties and allow for simulations that have been demonstrated to be coherent with data in literature. Results: Motivated by the need to address some aspects of the functioning of neural synapses, we have developed one such model for synaptic processes in the calyx of Held, which is a glutamatergic synapse in the auditory pathway of the mammalia. We have developed such a stochastic model starting from existing kinetic models based on ODEs of some sub-components of the synapse, integrating other data from literature and making some assumptions about non-fully understood processes. Experiments have confirmed the coherence of our model with known biological data, also validating the assumptions made. Our model overcomes some limitations of the kinetic ones and, to our knowledge, represents the first model of synaptic processes based on process calculi. The compositionality of the approach has permitted us to independently focus on tuning the models of the pre- and post- synaptic traits, and then to naturally connect them, by dealing with “interface” issues. Furthermore, we have improved the expressiveness of the model, e.g. by embedding easy control of element concentration time courses. Sensitivity analysis over several parameters of the model has provided results that may help clarify the dynamics of synaptic transmission, while experiments with the model of the complete synapse seem worth explaining short-term plasticity mechanisms. Conclusions: Specific presynaptic and postsynaptic mechanisms can be further analysed under various conditions, for instance by studying the presynaptic behaviour under repeated activations. The level of details of the description can be refined, for instance by further specifying the neurotransmitter generation and release steps. Taking advantage of the compositionality of the approach, an enhanced model could then be composed with other neural models, designed within the same framework, in order to obtain a more detailed and comprehensive model. In the long term, we are interested, in particular, in addressing models of synaptic plasticity, i.e. activity dependent mechanisms, which are the bases of memory and learning processes. More on the computer science side, we plan to follow some directions to improve the underlying computational model and the linguistic primitives it provides as suggested by the experiments carried out, e.g. by introducing a suitable notion of (spatial) locality

State of vegetative and cardiovascular system of Chornobyl nuclear accident liquidators

Проведено обследование 2-х групп больных с синдромом вегетативной дистонии (СВД): 1-я группа-57 учасникое ликвидации последствий аварии (ЛПА) на ЧАЭС, 2-я группа 22 больных с СВД невротического геиеза. У больных 1-й и 2-й групп выявлены признаки дисфункции неспецифиче ских регуляторных ( лимбико-ретикулярных) отделов мозга, которые проявляются СВД. Эти регуляторно-вегетативные нарушения, а также метаболические изменения приводят. к церебральной дисциркуляции и миокардиодистрофии, а в дальнейшем, к формированию атеросклероза. В этиопатогеиезе СВД у ЛПА на ЧАЭС ведущую роль играют психогенный и радиационный факторы.Проведено обстеження 2-х груп хворих із синдромом вегетативної дистонії (СВД): 1-а група - 57 учасників ліквідації наслідків аварії (ЛНА) на ЧАЕС, 2-а группа 22 хворих із СВД невротичного генезу. У хворих 1-ї та 2-ї групи виявлені ознаки дис функції неспецифічних регуляторних (лімбіко-ретикулярних) відділів мозку, які проявляються СВД. Ці регуляторно-вегетативні порушення, а також метаболічні зміни приводять до церебральної дисциркуляції і міокард іодистрофії, а в подальшому до фор мування атеросклерозу. В етіопатогенезі СВД у ЛНА на ЧАЕС провідну роль відіграють психогенний і радіаційний фактори.The Examination of 2 groups of patients with autonomic dystonia syndrome (VDS): Group 1 - 57 participants in the liquidation consequences of the Chernobyl accident (LNA), 2nd group of 22 patients with SVD of neurotic origin. At patients of the 1st and 2nd groups signs of dysfunction of nonspecific regulatory (limbic-reticular) departments of a brain which are shown by VDS are revealed. These are regulatory and vegetative disorders, as well as metabolic changes lead to cerebral dyscirculation and myocardial iodystrophy, and subsequently to the formation of atherosclerosis. Psychogenic and radiation factors play a leading role in the etiopathogenesis of SVD in LNA at the Chernobyl NPP