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      Miniature Neurotransmission Regulates Drosophila Synaptic Structural Maturation

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          Summary

          Miniature neurotransmission is the transsynaptic process where single synaptic vesicles spontaneously released from presynaptic neurons induce miniature postsynaptic potentials. Since their discovery over 60 years ago, miniature events have been found at every chemical synapse studied. However, the in vivo necessity for these small-amplitude events has remained enigmatic. Here, we show that miniature neurotransmission is required for the normal structural maturation of Drosophila glutamatergic synapses in a developmental role that is not shared by evoked neurotransmission. Conversely, we find that increasing miniature events is sufficient to induce synaptic terminal growth. We show that miniature neurotransmission acts locally at terminals to regulate synapse maturation via a Trio guanine nucleotide exchange factor (GEF) and Rac1 GTPase molecular signaling pathway. Our results establish that miniature neurotransmission, a universal but often-overlooked feature of synapses, has unique and essential functions in vivo.

          Highlights

          • Miniature, but not evoked, neurotransmission is required for synapse development

          • Miniature neurotransmission bidirectionally regulates synaptic terminal maturation

          • Miniature events signal locally through the GEF Trio and the GTPase Rac1

          • Miniature neurotransmission has unique and essential functions in vivo

          Abstract

          Miniature events (or “minis”) are a universal feature of all chemical synapses, but their function in vivo has remained enigmatic. Here, Choi et al. show that miniature neurotransmission is essential for synaptic terminal maturation in a role not shared by evoked neurotransmission.

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          Most cited references43

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          Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioral defects.

          Tetanus toxin cleaves the synaptic vesicle protein synaptobrevin, and the ensuing loss of neurotransmitter exocytosis has implicated synaptobrevin in this process. To further the study of synaptic function in a genetically tractable organism and to generate a tool to disable neuronal communication for behavioural studies, we have expressed a gene encoding tetanus toxin light chain in Drosophila. Toxin expression in embryonic neurons removes detectable synaptobrevin and eliminates evoked, but not spontaneous, synaptic vesicle release. No other developmental or morphological defects are detected. Correspondingly, only synaptobrevin (n-syb), but not the ubiquitously expressed syb protein, is cleaved by tetanus toxin in vitro. Targeted expression of toxin can produce specific behavioral defects; in one case, the olfactory escape response is reduced.
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            Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis.

            Activity deprivation in neurons induces a slow compensatory scaling up of synaptic strength, reflecting a homeostatic mechanism for stabilizing neuronal activity. Prior studies have focused on the loss of action potential (AP) driven neurotransmission in synaptic homeostasis. Here, we show that the miniature synaptic transmission that persists during AP blockade profoundly shapes the time course and mechanism of homeostatic scaling. A brief blockade of NMDA receptor (NMDAR) mediated miniature synaptic events ("minis") rapidly scales up synaptic strength, over an order of magnitude faster than with AP blockade alone. The rapid scaling induced by NMDAR mini blockade is mediated by increased synaptic expression of surface GluR1 and the transient incorporation of Ca2+-permeable AMPA receptors at synapses; both of these changes are implemented locally within dendrites and require dendritic protein synthesis. These results indicate that NMDAR signaling during miniature synaptic transmission serves to stabilize synaptic function through active suppression of dendritic protein synthesis.
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              wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila.

              We conducted a large-scale screen for Drosophila mutants that have structural abnormalities of the larval neuromuscular junction (NMJ). We recovered mutations in wishful thinking (wit), a gene that positively regulates synaptic growth. wit encodes a BMP type II receptor. In wit mutant larvae, the size of the NMJs is greatly reduced relative to the size of the muscles. wit NMJs have reduced evoked excitatory junctional potentials, decreased levels of the synaptic cell adhesion molecule Fasciclin II, and synaptic membrane detachment at active zones. Wit is expressed by a subset of neurons, including motoneurons. The NMJ phenotype is specifically rescued by transgenic expression of Wit only in motoneurons. Thus, Wit appears to function as a presynaptic receptor that regulates synaptic size at the Drosophila NMJ.
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                Author and article information

                Contributors
                Journal
                Neuron
                Neuron
                Neuron
                Cell Press
                0896-6273
                1097-4199
                07 May 2014
                07 May 2014
                : 82
                : 3
                : 618-634
                Affiliations
                [1 ]Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
                [2 ]Center for Motor Neuron Biology and Disease, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
                [3 ]Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
                [4 ]Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
                [5 ]Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK
                [6 ]Department of Cellular and Molecular Physiology, Department of Genetics, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale School of Medicine, New Haven, CT 06520, USA
                Author notes
                []Corresponding author brian@ 123456mccabelab.org
                Article
                S0896-6273(14)00207-4
                10.1016/j.neuron.2014.03.012
                4022839
                24811381
                fdf307b6-272e-4b04-bd17-29e44841c1cc
                © 2014 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                : 18 February 2014
                Categories
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                Neurosciences
                Neurosciences

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