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      Homeostatic control of Drosophila neuromuscular junction function

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          Abstract

          The ability to adapt to changing internal and external conditions is a key feature of biological systems. Homeostasis refers to a regulatory process that stabilizes dynamic systems to counteract perturbations. In the nervous system, homeostatic mechanisms control neuronal excitability, neurotransmitter release, neurotransmitter receptors, and neural circuit function. The neuromuscular junction (NMJ) of Drosophila melanogaster has provided a wealth of molecular information about how synapses implement homeostatic forms of synaptic plasticity, with a focus on the transsynaptic, homeostatic modulation of neurotransmitter release. This review examines some of the recent findings from the Drosophila NMJ and highlights questions the field will ponder in coming years.

          Abstract

          At the larval Drosophila neuromuscular junction (NMJ), neurotransmitter receptor (blue) perturbation in the muscle cell (gray cylinder) enhances neurotransmitter release (green, “Presynaptic homeostatic potentiation”, PHP) from the motor neuron. This review summarizes recent updates on this evolutionarily conserved form of transsynaptic plasticity.

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          Most cited references81

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          The self-tuning neuron: synaptic scaling of excitatory synapses.

          Homeostatic synaptic scaling is a form of synaptic plasticity that adjusts the strength of all of a neuron's excitatory synapses up or down to stabilize firing. Current evidence suggests that neurons detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional mechanisms may allow local or network-wide changes in activity to be sensed through parallel pathways, generating a nested set of homeostatic mechanisms that operate over different temporal and spatial scales.
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            Variability, compensation and homeostasis in neuron and network function.

            Neurons in most animals live a very long time relative to the half-lives of all of the proteins that govern excitability and synaptic transmission. Consequently, homeostatic mechanisms are necessary to ensure stable neuronal and network function over an animal's lifetime. To understand how these homeostatic mechanisms might function, it is crucial to understand how tightly regulated synaptic and intrinsic properties must be for adequate network performance, and the extent to which compensatory mechanisms allow for multiple solutions to the production of similar behaviour. Here, we use examples from theoretical and experimental studies of invertebrates and vertebrates to explore several issues relevant to understanding the precision of tuning of synaptic and intrinsic currents for the operation of functional neuronal circuits.
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              Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis.

              Synapses are asymmetric cellular adhesions that are critical for nervous system development and function, but the mechanisms that induce their formation are not well understood. We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of alpha2delta-1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. alpha2delta-1 overexpression increases synaptogenesis in vitro and in vivo and is required postsynaptically for thrombospondin- and astrocyte-induced synapse formation in vitro. Gabapentin antagonizes thrombospondin binding to alpha2delta-1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify alpha2delta-1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.
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                Author and article information

                Contributors
                Martin.Mueller@imls.uzh.ch
                Journal
                Synapse
                Synapse
                10.1002/(ISSN)1098-2396
                SYN
                Synapse (New York, N.y.)
                John Wiley and Sons Inc. (Hoboken )
                0887-4476
                1098-2396
                04 October 2019
                January 2020
                : 74
                : 1 ( doiID: 10.1002/syn.v74.1 )
                : e22133
                Affiliations
                [ 1 ] Department of Anatomy and Cell Biology University of Iowa Carver College of Medicine Iowa City Iowa USA
                [ 2 ] Interdisciplinary Programs in Neuroscience, Genetics, and Molecular Medicine University of Iowa Iowa City Iowa USA
                [ 3 ] Interdisciplinary Graduate Program in Neuroscience University of Iowa Iowa City Iowa USA
                [ 4 ] Institute of Molecular Life Sciences University of Zurich Zurich Switzerland
                [ 5 ] Neuroscience Center Zurich Zurich Switzerland
                [ 6 ]Present address: Department of Neuroscience and Pharmacology University of Iowa Carver College of Medicine Iowa City Iowa USA
                Author notes
                [*] [* ] Correspondence

                Martin Müller, Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland.

                Email: Martin.Mueller@ 123456imls.uzh.ch

                Author information
                https://orcid.org/0000-0001-9599-421X
                https://orcid.org/0000-0003-0949-4783
                https://orcid.org/0000-0003-1624-6761
                Article
                SYN22133
                10.1002/syn.22133
                6817395
                31556149
                db7e93b0-36ca-4800-a0d3-0721919bef0e
                © 2019 The Authors. Synapse published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 July 2019
                : 05 September 2019
                : 19 September 2019
                Page count
                Figures: 4, Tables: 0, Pages: 13, Words: 27192
                Funding
                Funded by: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung , open-funder-registry 10.13039/501100001711;
                Award ID: PP00P3_144816
                Funded by: H2020 European Research Council , open-funder-registry 10.13039/100010663;
                Award ID: 679881
                Funded by: National Science Foundation , open-funder-registry 10.13039/100000001;
                Award ID: 1557792
                Funded by: National Institute of Neurological Disorders and Stroke , open-funder-registry 10.13039/100000065;
                Award ID: R01NS085164
                Award ID: T32NS007421
                Categories
                Review Article
                Review Article
                Custom metadata
                2.0
                January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019

                Neurosciences
                homeostatic plasticity,neurotransmitter release,presynaptic mechanisms,synaptic plasticity,transsynaptic signalling

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