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Rodriguez-Arellano J.J.,Ikerbasque | Rodriguez-Arellano J.J.,University of the Basque Country | Parpura V.,Evelyn F Mcknight Brain Institute Atomic Force Microscopy And Nanotechnology Laboratories | Parpura V.,University of Rijeka | And 7 more authors.
Neuroscience | Year: 2016

Astrocytes are fundamental for homoeostasis, defence and regeneration of the central nervous system. Loss of astroglial function and astroglial reactivity contributes to the aging of the brain and to neurodegenerative diseases. Changes in astroglia in aging and neurodegeneration are highly heterogeneous and region-specific. In animal models of Alzheimer's disease (AD) astrocytes undergo degeneration and atrophy at the early stages of pathological progression, which possibly may alter the homeostatic reserve of the brain and contribute to early cognitive deficits. At later stages of AD reactive astrocytes are associated with neurite plaques, the feature commonly found in animal models and in human diseased tissue. In animal models of the AD reactive astrogliosis develops in some (e.g. in the hippocampus) but not in all regions of the brain. For instance, in entorhinal and prefrontal cortices astrocytes do not mount gliotic response to emerging β-amyloid deposits. These deficits in reactivity coincide with higher vulnerability of these regions to AD-type pathology. Astroglial morphology and function can be regulated through environmental stimulation and/or medication suggesting that astrocytes can be regarded as a target for therapies aimed at the prevention and cure of neurodegenerative disorders. © 2015 IBRO.


Zorec R.,University of Ljubljana | Zorec R.,Technology Park Ljubljana | Verkhratsky A.,University of Ljubljana | Verkhratsky A.,Technology Park Ljubljana | And 7 more authors.
Neuroscience | Year: 2016

Neurotransmitters released at synapses activate neighboring astrocytes, which in turn, modulate neuronal activity by the release of diverse neuroactive substances that include classical neurotransmitters such as glutamate, GABA or ATP. Neuroactive substances are released from astrocytes through several distinct molecular mechanisms, for example, by diffusion through membrane channels, by translocation via plasmalemmal transporters or by vesicular exocytosis. Vesicular release regulated by a stimulus-mediated increase in cytosolic calcium involves soluble N-ethyl maleimide-sensitive fusion protein attachment protein receptor (SNARE)-dependent merger of the vesicle membrane with the plasmalemma. Up to 25 molecules of synaptobrevin 2 (Sb2), a SNARE complex protein, reside at a single astroglial vesicle; an individual neuronal, i.e. synaptic, vesicle contains ~70 Sb2 molecules. It is proposed that this paucity of Sb2 molecules in astrocytic vesicles may determine the slow secretion. In the present essay we shall overview multiple aspects of vesicular architecture and types of vesicles based on their cargo and dynamics in astroglial cells. © 2015 IBRO.


Vandenbeuch A.,University of Colorado at Denver | Zorec R.,University of Ljubljana | Zorec R.,Technology Park Ljubljana | Kinnamon S.C.,University of Colorado at Denver
Journal of Neuroscience | Year: 2010

Exocytosis, consisting of the merger of vesicle and plasma membrane, is a common mechanism used by different types of nucleated cells to release their vesicular contents. Taste cells possess vesicles containing various neurotransmitters to communicate with adjacent taste cells and afferent nerve fibers. However, whether these vesicles engage in exocytosis on a stimulus is not known. Since vesicle membrane merger with the plasma membrane is reflected in plasma membrane area fluctuations, we measured membrane capacitance (C m), a parameter linearly related to membrane surface area. To investigate whether taste cells undergo regulated exocytosis, we used the compensated tight-seal whole-cell recording technique to monitor depolarization-induced changes in C m in the different types of taste cells. To identify taste cell types, mice expressing green fluorescent protein from the TRPM5 promoter or from the GAD67 promoter were used to discriminate type II and type III taste cells, respectively. Moreover, the cell types were also identified by monitoring their voltage-current properties. The results demonstrate that only type III taste cells show significant depolarization- induced increases in C m, which were correlated to the voltage-activated calcium currents. The results suggest that type III, but neither type II nor type I cells exhibit depolarization-induced regulated exocytosis to release transmitter and activate gustatory afferent nerve fibers. Copyright © 2010 the authors.


Verkhratsky A.,University of Manchester | Verkhratsky A.,Ikerbasque | Verkhratsky A.,University of the Basque Country | Verkhratsky A.,Nizhny Novgorod State Technical University | And 5 more authors.
Current Opinion in Pharmacology | Year: 2016

Ageing of the brain is the major risk factor for neurodegenerative disorders that result in cognitive decline and senile dementia. Ageing astrocytes undergo complex and region specific remodelling which can reflect life-long adaptive plasticity. In neurodegeneration, astroglial cells are similarly a subject for morpho-functional changes hampering the homoeostasis, defence and regeneration of the central nervous system. Region-specific astroglial atrophy with the loss of function and astroglial reactivity have been reported in virtually all forms of neurodegenerative pathologies. Modulating these astroglia changes may represent a fertile ground for novel therapeutic intervention strategies to prevent, delay progression and/or ameliorate pathology. While at present this bodacious goal represents a wishful thinking, further understanding of astroglial role in ageing and neurodegeneration could bring us closer to laying the foundations for such cell-specific therapeutic approaches. © 2015 Elsevier Ltd. All rights reserved.


Parpura V.,University of Alabama at Birmingham | Baker B.J.,University of Alabama at Birmingham | Jeras M.,University of Ljubljana | Jeras M.,Technology Park Ljubljana | And 2 more authors.
Neurochemistry International | Year: 2010

Astrocytes can be considered as signal integrators in central nervous system activity. These glial cells can respond to signals from the heterocellular milieu of the brain and subsequently release various molecules to signal to themselves and/or other neighboring neural cells. An important functional module that enables signal integration in astrocytes is exocytosis, a Ca2+-dependent process consisting of vesicular fusion to the plasma membrane. Astrocytes utilize regulated exocytosis to release various signaling molecules stored in the vesicular lumen. Here we review the properties of exocytotic release of three classes of gliotransmitters: (i) amino acids, (ii) nucleotides and (iii) peptides. Vesicles may carry not only lumenal cargo, but also membrane-associated molecules. Therefore, we also discuss exocytosis as a delivery mechanism for transporters and receptors to the plasma membrane, where these proteins are involved in astrocytic intercellular signaling. © 2010 Elsevier Ltd.


Parpura V.,University of Alabama at Birmingham | Zorec R.,University of Ljubljana | Zorec R.,Technology Park Ljubljana
Brain Research Reviews | Year: 2010

Gliotransmitters are chemicals released from glial cells fulfilling a following set of criteria: (i) they are synthesized by and/or stored in glia; (ii) their regulated release is triggered by physiological and/or pathological stimuli; (iii) they activate rapid (milliseconds to seconds) responses in neighboring cells; and (iv) they play a role in (patho)physiological processes. Astrocytes can release a variety of gliotransmitters into the extracellular space using several different mechanisms. In this review, we focus on exocytotic mechanism(s) underlying the release of three classes of gliotransmitters: (i) amino acids, such as, glutamate and d-serine; (ii) nucleotides, like adenosine 5'-triphosphate; and (iii) peptides, such as, atrial natriuretic peptide and brain-derived neurotrophic factor. It is becoming clear that astrocytes are endowed with elements that qualify them as cells communicating with neurons and other cells within the central nervous system by employing regulated exocytosis. © 2009 Elsevier B.V.


Grabec I.,Technology Park Ljubljana
Nonlinear Phenomena in Complex Systems | Year: 2010

Statistical modeling of physical laws connects experiments with mathematical descriptions of natural phenomena. Most general modeling is based on nonparametric estimation of the probability density from statistical samples of measured variables. For this purpose a kernel estimator is utilized in the article. As an objective kernel the scattering function determined by calibration of the instrument is introduced. This function provides for a definition of experimental information and redundancy of experimentation in terms of information entropy. The redundancy increases with the number of experiments, while the experimental information converges to a value that describes the complexity of the data. The difference between the redundancy and the experimental information is proposed as the model cost function. From its minimum, a proper number of data needed for modeling is estimated. As an optimal, nonparametric estimator of the relation between measured variables the conditional average extracted from the kernel estimator is proposed. The modeling is demonstrated on noisy chaotic data.


Grabec I.,Technology Park Ljubljana
Neural Networks | Year: 2013

This article deals with experimental description of physical laws by probability density function of measured data. The Gaussian mixture model specified by representative data and related probabilities is utilized for this purpose. The information cost function of the model is described in terms of information entropy by the sum of the estimation error and redundancy. A new method is proposed for searching the minimum of the cost function. The number of the resulting prototype data depends on the accuracy of measurement. Their adaptation resembles a self-organized, highly non-linear cooperation between neurons in an artificial NN. A prototype datum corresponds to the memorized content, while the related probability corresponds to the excitability of the neuron. The method does not include any free parameters except objectively determined accuracy of the measurement system and is therefore convenient for autonomous execution. Since representative data are generally less numerous than the measured ones, the method is applicable for a rather general and objective compression of overwhelming experimental data in automatic data-acquisition systems. Such compression is demonstrated on analytically determined random noise and measured traffic flow data. The flow over a day is described by a vector of 24 components. The set of 365 vectors measured over one year is compressed by autonomous learning to just 4 representative vectors and related probabilities. These vectors represent the flow in normal working days and weekends or holidays, while the related probabilities correspond to relative frequencies of these days. This example reveals that autonomous learning yields a new basis for interpretation of representative data and the optimal model structure. © 2012 Elsevier Ltd.


Grabec I.,Technology Park Ljubljana
Nonlinear Phenomena in Complex Systems | Year: 2011

Redundancy of experimental data is the basic statistic from which the complexity of a natural phenomenon and the proper number of experiments needed for its exploration can be estimated. The redundancy is expressed by the entropy of information pertaining to the probability density function of experimental variables. Since the calculation of entropy is inconvenient due to integration over a range of variables, an approximate expression for redundancy is derived that includes only a sum over the set of experimental data about these variables. The approximation makes feasible an efficient estimation of the redundancy of data along with the related experimental information and information cost function. From the experimental information the complexity of the phenomenon can be simply estimated, while the proper number of experiments needed for its exploration can be determined from the minimum of the cost function. The performance of the approximate estimation of these statistics is demonstrated on two-dimensional normally distributed random data.


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