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      A Purinergic P2 Receptor Family-Mediated Increase in Thrombospondin-1 Bolsters Synaptic Density and Epileptic Seizure Activity in the Amygdala-Kindling Rat Model

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          Abstract

          Previous studies suggested that the thrombospondin-1/transforming growth factor-β1 (TSP-1/TGF-β1) pathway might be critical in synaptogenesis during development and that the purinergic P2 receptor family could regulate synaptogenesis by modulating TSP-1 signaling. However, it is unclear whether this pathway plays a role in synaptogenesis during epileptic progression. This study was designed to investigate this question by analyzing the dynamic changes and effects of TSP-1 levels on the density of synaptic markers that are related to epileptic seizure activity. In addition, we evaluated whether P2-type receptors could regulate these effects. We generated a rat seizure model via amygdala kindling and inhibited TSP-1 activity using small interfering RNA (siRNA) interference and pharmacological inhibition. We treated the rats with antagonists of P2 or P2Y receptors, pyridoxalphosphate-6-azophenyl-2’,4’-disulfonic (PPADS) or Reactive Blue 2. Following this, we quantified TSP-1 and TGF-β1 immunoreactivity (IR), the density of synaptic markers, and seizure activity. There were significantly more synapses/excitatory synapses in several brain regions, such as the hippocampus, which were associated with progressing epileptic discharges after kindling. These were associated with increased TSP-1 and TGF-β1-IR. Genetic or pharmacologic inhibition of TSP-1 significantly reduced the density of synaptic/excitatory synaptic markers and inhibited the generalization of focal epilepsy. The administration of PPADS or Reactive Blue 2 attenuated the increase in TSP-1-IR and the increase in the density of synaptic markers that follows kindling and abolished most of the epileptic seizure activity. Altogether, our results indicate that the TSP-1/TGF-β1 pathway and its regulation by P2, particularly P2Y-type receptors, may be a critical promoter of synaptogenesis during the progression of epilepsy. Therefore, components of this pathway may be targets for novel antiepileptic drug development.

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          Most cited references61

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          Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis.

          The establishment of neural circuitry requires vast numbers of synapses to be generated during a specific window of brain development, but it is not known why the developing mammalian brain has a much greater capacity to generate new synapses than the adult brain. Here we report that immature but not mature astrocytes express thrombospondins (TSPs)-1 and -2 and that these TSPs promote CNS synaptogenesis in vitro and in vivo. TSPs induce ultrastructurally normal synapses that are presynaptically active but postsynaptically silent and work in concert with other, as yet unidentified, astrocyte-derived signals to produce functional synapses. These studies identify TSPs as CNS synaptogenic proteins, provide evidence that astrocytes are important contributors to synaptogenesis within the developing CNS, and suggest that TSP-1 and -2 act as a permissive switch that times CNS synaptogenesis by enabling neuronal molecules to assemble into synapses within a specific window of CNS development.
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            ATP as a multi-target danger signal in the brain

            ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, in astrocyte-to-neuron communication, propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R) as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR), which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.
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              Surface diffusion of astrocytic glutamate transporters shapes synaptic transmission.

              Control of the glutamate time course in the synapse is crucial for excitatory transmission. This process is mainly ensured by astrocytic transporters, high expression of which is essential to compensate for their slow transport cycle. Although molecular mechanisms regulating transporter intracellular trafficking have been identified, the relationship between surface transporter dynamics and synaptic function remains unexplored. We found that GLT-1 transporters were highly mobile on rat astrocytes. Surface diffusion of GLT-1 was sensitive to neuronal and glial activities and was strongly reduced in the vicinity of glutamatergic synapses, favoring transporter retention. Notably, glutamate uncaging at synaptic sites increased GLT-1 diffusion, displacing transporters away from this compartment. Functionally, impairing GLT-1 membrane diffusion through cross-linking in vitro and in vivo slowed the kinetics of excitatory postsynaptic currents, indicative of a prolonged time course of synaptic glutamate. These data provide, to the best of our knowledge, the first evidence for a physiological role of GLT-1 surface diffusion in shaping synaptic transmission.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                01 October 2018
                2018
                : 12
                : 302
                Affiliations
                [1] 1School of Pharmaceutical Sciences, Binzhou Medical University Yantai, China
                [2] 2Shandong Academy of Medical Sciences (SDAMS) Jinan, China
                Author notes

                Edited by: Carl E. Stafstrom, Johns Hopkins Medicine, United States

                Reviewed by: Rodrigo A. Cunha, Universidade de Coimbra, Portugal; Ji Won Um, Daegu Gyeongbuk Institute of Science and Technology (DGIST), South Korea

                *Correspondence: Qiaoyun Wang sun_chinese@ 123456163.com Wei Zhu fsszw@ 123456163.com

                These authors have contributed equally to this work

                Article
                10.3389/fncel.2018.00302
                6199899
                30386206
                17dc814f-a738-46e0-a9e0-f18f9ebb9d6c
                Copyright © 2018 Sun, Ma, Zhang, Pan, Wang, Zhang, Zhang, Sun, Wang and Zhu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 11 April 2018
                : 20 August 2018
                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 66, Pages: 12, Words: 7967
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81573412
                Funded by: Natural Science Foundation of Shandong Province 10.13039/501100007129
                Award ID: ZR2015HM013, ZR2014JL055
                Categories
                Neuroscience
                Original Research

                Neurosciences
                thrombospondin-1,purinergic receptor 2,synapse,epileptogenesis,astrocyte
                Neurosciences
                thrombospondin-1, purinergic receptor 2, synapse, epileptogenesis, astrocyte

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