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      Novel astrocyte targets : New Avenues for the Therapeutic Treatment of Epilepsy

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          Abstract

          During the last 20 years, it has been well established that a finely tuned, continuous crosstalk between neurons and astrocytes not only critically modulates physiological brain functions but also underlies many neurological diseases. In particular, this novel way of interpreting brain activity is markedly influencing our current knowledge of epilepsy, prompting a re-evaluation of old findings and guiding novel experimentation. Here, we review recent studies that have unraveled novel and unique contributions of astrocytes to the generation and spread of convulsive and nonconvulsive seizures and epileptiform activity. The emerging scenario advocates an overall framework in which a dynamic and reciprocal interplay among astrocytic and neuronal ensembles is fundamental for a fuller understanding of epilepsy. In turn, this offers novel astrocytic targets for the development of those really novel chemical entities for the control of convulsive and nonconvulsive seizures that have been acknowledged as a key priority in the management of epilepsy.

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          Most cited references211

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          Astrocytic purinergic signaling coordinates synaptic networks.

          To investigate the role of astrocytes in regulating synaptic transmission, we generated inducible transgenic mice that express a dominant-negative SNARE domain selectively in astrocytes to block the release of transmitters from these glial cells. By releasing adenosine triphosphate, which accumulates as adenosine, astrocytes tonically suppressed synaptic transmission, thereby enhancing the dynamic range for long-term potentiation and mediated activity-dependent, heterosynaptic depression. These results indicate that astrocytes are intricately linked in the regulation of synaptic strength and plasticity and provide a pathway for synaptic cross-talk.
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            Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1.

            Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.
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              Astrocyte control of synaptic transmission and neurovascular coupling.

              From a structural perspective, the predominant glial cell of the central nervous system, the astrocyte, is positioned to regulate synaptic transmission and neurovascular coupling: the processes of one astrocyte contact tens of thousands of synapses, while other processes of the same cell form endfeet on capillaries and arterioles. The application of subcellular imaging of Ca2+ signaling to astrocytes now provides functional data to support this structural notion. Astrocytes express receptors for many neurotransmitters, and their activation leads to oscillations in internal Ca2+. These oscillations induce the accumulation of arachidonic acid and the release of the chemical transmitters glutamate, d-serine, and ATP. Ca2+ oscillations in astrocytic endfeet can control cerebral microcirculation through the arachidonic acid metabolites prostaglandin E2 and epoxyeicosatrienoic acids that induce arteriole dilation, and 20-HETE that induces arteriole constriction. In addition to actions on the vasculature, the release of chemical transmitters from astrocytes regulates neuronal function. Astrocyte-derived glutamate, which preferentially acts on extrasynaptic receptors, can promote neuronal synchrony, enhance neuronal excitability, and modulate synaptic transmission. Astrocyte-derived d-serine, by acting on the glycine-binding site of the N-methyl-d-aspartate receptor, can modulate synaptic plasticity. Astrocyte-derived ATP, which is hydrolyzed to adenosine in the extracellular space, has inhibitory actions and mediates synaptic cross-talk underlying heterosynaptic depression. Now that we appreciate this range of actions of astrocytic signaling, some of the immediate challenges are to determine how the astrocyte regulates neuronal integration and how both excitatory (glutamate) and inhibitory signals (adenosine) provided by the same glial cell act in concert to regulate neuronal function.
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                Author and article information

                Journal
                Neuroscientist
                Neuroscientist
                NRO
                spnro
                The Neuroscientist
                SAGE Publications (Sage CA: Los Angeles, CA )
                1073-8584
                1089-4098
                February 2015
                February 2015
                : 21
                : 1
                : 62-83
                Affiliations
                [1 ]Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, UK
                [2 ]Centro Nazionale della Ricerca, Neuroscience Institute and Department of Biomedical Sciences, University of Padova, Padova, Italy
                [3 ]Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany
                Author notes
                [*]Vincenzo Crunelli, Neuroscience Division, School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK. Email: crunelli@ 123456cardiff.ac.uk
                Article
                10.1177_1073858414523320
                10.1177/1073858414523320
                4361461
                24609207
                7840ad50-defd-45f0-8c4a-98209c2a82c1
                © The Author(s) 2014

                This article is distributed under the terms of the Creative Commons Attribution 3.0 License ( http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( http://www.uk.sagepub.com/aboutus/openaccess.htm).

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                glutamate,gaba,connexin,potassium,temporal lobe epilepsy,absence epilepsy

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