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      Müller Glial Cells Participate in Retinal Waves via Glutamate Transporters and AMPA Receptors

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          SUMMARY

          Retinal waves, the spontaneous patterned neural activities propagating among developing retinal ganglion cells (RGCs), instruct the activity-dependent refinement of visuotopic maps. Although it is known that the wave is initiated successively by amacrine cells and bipolar cells, the behavior and function of glia in retinal waves remain unclear. Using multiple in vivo methods in larval zebrafish, we found that Müller glial cells (MGCs) display wave-like spontaneous activities, which start at MGC processes within the inner plexiform layer, vertically spread to their somata and endfeet, and horizontally propagate into neighboring MGCs. MGC waves depend on glutamatergic signaling derived from bipolar cells. Moreover, MGCs express both glia-specific glutamate transporters and the AMPA subtype of glutamate receptors. The AMPA receptors mediate MGC calcium activities during retinal waves, whereas the glutamate transporters modulate the occurrence of retinal waves. Thus, MGCs can sense and regulate retinal waves via AMPA receptors and glutamate transporters, respectively.

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          In Brief

          The behavior and function of glial cells in spontaneous retinal waves remain unclear. Using in vivo calcium imaging and electrophysiological recording in larval zebrafish, Zhang et al. show that Müller glial cells can participate in and modulate retinal waves, respectively, via AMPA receptors and glutamate transporters on their own processes.

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          Most cited references51

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          AMPA receptor trafficking and synaptic plasticity.

          Activity-dependent changes in synaptic function are believed to underlie the formation of memories. Two prominent examples are long-term potentiation (LTP) and long-term depression (LTD), whose mechanisms have been the subject of considerable scrutiny over the past few decades. Here we review the growing literature that supports a critical role for AMPA receptor trafficking in LTP and LTD, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins. While much work remains to understand the molecular basis for synaptic plasticity, recent results on AMPA receptor trafficking provide a clear conceptual framework for future studies.
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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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              Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.

              Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein. Animal studies show that the protein is important for normal excitatory synaptic transmission, while its dysfunction is implicated in acute and chronic neurological disorders, including amyotrophic lateral sclerosis (ALS), stroke, brain tumours and epilepsy. Using a blinded screen of 1,040 FDA-approved drugs and nutritionals, we discovered that many beta-lactam antibiotics are potent stimulators of GLT1 expression. Furthermore, this action appears to be mediated through increased transcription of the GLT1 gene. beta-Lactams and various semi-synthetic derivatives are potent antibiotics that act to inhibit bacterial synthetic pathways. When delivered to animals, the beta-lactam ceftriaxone increased both brain expression of GLT1 and its biochemical and functional activity. Glutamate transporters are important in preventing glutamate neurotoxicity. Ceftriaxone was neuroprotective in vitro when used in models of ischaemic injury and motor neuron degeneration, both based in part on glutamate toxicity. When used in an animal model of the fatal disease ALS, the drug delayed loss of neurons and muscle strength, and increased mouse survival. Thus these studies provide a class of potential neurotherapeutics that act to modulate the expression of glutamate neurotransmitter transporters via gene activation.
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                Author and article information

                Journal
                101573691
                39703
                Cell Rep
                Cell Rep
                Cell reports
                2211-1247
                12 July 2019
                04 June 2019
                26 July 2019
                : 27
                : 10
                : 2871-2880.e2
                Affiliations
                [1 ]Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China
                [2 ]School of Life Science and Technology, ShanghaiTech University, 319 Yue-Yang Road, Shanghai 200031, China
                [3 ]School of Future Technology, University of Chinese Academy of Sciences, 19A Yu-Quan Road, Beijing 100049, China
                [4 ]Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
                [5 ]Lead Contact
                Author notes

                AUTHOR CONTRIBUTIONS

                R.-W.Z. and J.-L.D. conceived the project and designed the experiments. R.-W.Z. and W.-J.D. performed the research and analyzed the data. D.A.P. provided some experimental reagents. R.-W.Z. and J.-L.D. wrote the paper.

                [* ]Correspondence: rongweizhang@ 123456gmail.com (R.-w.Z.), forestdu@ 123456ion.ac.cn (J.-l.D.)
                Article
                NIHMS1534459
                10.1016/j.celrep.2019.05.011
                6659749
                31167134
                19e29679-2375-4875-96e4-eadcebc8e094

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                Cell biology
                Cell biology

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