Activity-dependent regulation of astrocyte GAT levels during synaptogenesis

Muthukumar, Allie K.; Stork, Tobias; Freeman, Marc

doi:10.1038/nn.3791

Cited by 128 publications

(177 citation statements)

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“…The subset of Drosophila glial cells examined in this study has been named 'interface glia' (Ito et al, 1995), 'longitudinal glia' (Beckervordersandforth et al, 2008), 'astrocyte-like glia' (Awasaki et al, 2008), and, most recently, just 'astrocytes' Muthukumar et al, 2014;Peco et al, 2016), based on their morphology and molecular identity. The present study is the first to characterize the electrical membrane properties of Drosophila astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular evidence indicates that fly astrocytes express neurotransmitter transporters (glutamate transporter, Eaat1, and GABA transporter, Gat) (Rival et al, 2004;Thimgan et al, 2006) and receptors (metabotropic GABA receptors) (Mezler et al, 2001;Muthukumar et al, 2014), as well as gap-junction forming innexins (Stebbings et al, 2002), much like their mammalian counterparts (Kimelberg and Nedergaard, 2010). Several complex behaviors have been shown to be influenced by genes expressed in Drosophila astrocytes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Astrocytic glutamate transport regulates a Drosophila CNS synapse that lacks astrocyte ensheathment

MacNamee

Liu

Gerhard

et al. 2016

J of Comparative Neurology

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Anatomical, molecular, and physiological interactions between astrocytes and neuronal synapses regulate information processing in the brain. The fruit fly Drosophila melanogaster has become a valuable experimental system for genetic manipulation of the nervous system and has enormous potential for elucidating mechanisms that mediate neuron glia interactions. Here, we show the first electrophysiological recordings from Drosophila astrocytes and characterize their spatial and physiological relationship with particular synapses. Astrocyte intrinsic properties were found to be strongly analogous to those of vertebrate astrocytes, including a passive current-voltage relationship, low membrane resistance, high capacitance, and dye-coupling to local astrocytes. Responses to optogenetic stimulation of glutamatergic pre-motor neurons were correlated directly with anatomy using serial electron microscopy reconstructions of homologous identified neurons and surrounding astrocytic processes. Robust bidirectional communication was present: neuronal activation triggered astrocytic glutamate transport via Eaat1, and blocking Eaat1 extended glutamatergic interneuron-evoked inhibitory post-synaptic currents in motor neurons. The neuronal synapses were always located within a micron of an astrocytic process, but none were ensheathed by those processes. Thus, fly astrocytes can modulate fast synaptic transmission via neurotransmitter transport within these anatomical parameters. Graphical AbstractCorresponding Author: Sarah E. MacNamee, University of Arizona Dept. of Neuroscience, 1040 E 4 th St GS Rm 611, Tucson AZ 85721, (520) 621 6671, Smac3@email.arizona.edu. Role of AuthorsAll authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: SEM, LAO. Acquisition of data: SEM, KEL, SG, CTT, RDF, AC. Analysis and interpretation of data: SEM, KEL, CTT. Drafting of the manuscript: SEM. Critical revision of the manuscript for important intellectual content: LAO, LPT, AC. Statistical analysis: SEM. Obtained funding: LAO, LPT, AC. Administrative, technical, and material support: none. Study supervision: LAO, LPT. Conflict of Interest StatementThe authors have no conflict of interest to disclose. Data AccessibilityData generated in the lab and the subsequent analyses will be made available upon request to the Oland/Tolbert laboratory by qualified individuals as long as doing so would not compromise intellectual property interests or interfere with publication. Any shared data would include notations, standards, and the like that are necessary for interpretation of the data. HHMI Author Manuscript HHMI Author Manuscript HHMI Author ManuscriptThe authors show the first recordings from Drosophila astrocytes and find that their electrophysiological properties are strongly analogous to those of vertebrate astrocytes. Using correlative electron microscopy and physiology, they found no glial ensheathment of glutamatergic synap...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Astrocytic glutamate transport regulates a Drosophila CNS synapse that lacks astrocyte ensheathment

MacNamee

Liu

Gerhard

et al. 2016

J of Comparative Neurology

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“…2) (Awasaki et al 2008;Doherty et al 2009;Muthukumar et al 2014;Stork et al 2014;Tasdemir-Yilmaz and Freeman 2014). Of the three glial subtypes discussed in this chapter astrocytes by far are the most heavily studied.…”

Section: Astrocytesmentioning

confidence: 99%

“…The cell body and primary branches of astrocytes are microtubule (MT)-rich with MT plus ends oriented toward the fine processes, which are actin rich ). In the larval and adult nervous system, these cells seem to extend processes that cover the vast majority of the neuropil synaptic space (Muthukumar et al 2014;Stork et al 2014). Astrocytes appear to talk to one another to ensure full coverage of the neuropil.…”

Section: Astrocytesmentioning

confidence: 99%

DrosophilaCentral Nervous System Glia

Freeman

2015

Cold Spring Harb Perspect Biol

265

282

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Molecular genetic approaches in small model organisms like Drosophila have helped to elucidate fundamental principles of neuronal cell biology. Much less is understood about glial cells, although interest in using invertebrate preparations to define their in vivo functions has increased significantly in recent years. This review focuses on our current understanding of the three major neuron-associated glial cell types found in the Drosophila central nervous system (CNS)-astrocytes, cortex glia, and ensheathing glia. Together, these cells act like mammalian astrocytes: they surround neuronal cell bodies and proximal neurites, are coupled to the vasculature, and associate closely with synapses. Exciting recent work has shown essential roles for these CNS glial cells in neural circuit formation, function, plasticity, and pathology. As we gain a more firm molecular and cellular understanding of how Drosophila CNS glial cells interact with neurons, it is becoming clear they share significant molecular and functional attributes with mammalian astrocytes. Invertebrate preparations have contributed enormously to our understanding of fundamental principles of nervous system biology, including the chemical and electrophysiological basis of the action potential, synaptic vesicle release, neural cell fate specification, and axon pathfinding. This is largely thanks to the high experimental accessibility, ease of culture, rapid growth, and the panoply of molecular genetic tools with which to manipulate individual cells in vivo in organisms like Drosophila and Caenorhabditis elegans. The focus of many neuroscientists has shifted in recent years toward careful exploration of how glial cells participate in nervous system development, neural circuit function and plasticity, and neurological disease. Based on the remarkable success with which invertebrates were used to dissect fundamental aspects of the cell biology of the neuron, interest in the potential of small genetic model organisms to contribute to unraveling the mysteries of glial cells has grown significantly. This article will provide a brief overview of Drosophila glial cell biology, then focus on fly glial cell subtypes that are tightly associated with neurons in the central nervous system (CNS)-astrocytes, ensheathing glia, and cortex glia. A growing body of work argues strongly that these glia share a range morphological and functional features with mammalian astrocytes, and recent molecular studies indicate that conservation of basic glial cell biology extends, perhaps not surprisingly, to the molecular level.

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“…Drosophila astrocytes respond to neuronal activity with altered transporter expression and intracellular calcium dynamics (Muthukumar et al, 2014;Stork et al, 2014), they influence CNS synapse number during neural circuit formation (Muthukumar et al, 2014) and modulate locomotor behavior, seizures and olfactory processing (Liu et al, 2014;Rival et al, 2004;Stacey et al, 2010;Stork et al, 2014). However, little is known about how Drosophila astrocytes are organized relative to specific regions of the synaptic neuropil, or of the key regulatory programs that govern the acquisition of astrocyte fate versus that of other glial cell types.…”

Section: Introductionmentioning

confidence: 99%

Drosophila astrocytes cover specific territories of CNS neuropil and are instructed to differentiate by Prospero, a key effector of Notch

et al. 2016

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Astrocytes are crucial in the formation, fine-tuning, function and plasticity of neural circuits in the central nervous system. However, important questions remain about the mechanisms instructing astrocyte cell fate. We have studied astrogenesis in the ventral nerve cord of Drosophila larvae, where astrocytes exhibit remarkable morphological and molecular similarities to those in mammals. We reveal the births of larval astrocytes from a multipotent glial lineage, their allocation to reproducible positions, and their deployment of ramified arbors to cover specific neuropil territories to form a stereotyped astroglial map. Finally, we unraveled a molecular pathway for astrocyte differentiation in which the Ets protein Pointed and the Notch signaling pathway are required for astrogenesis; however, only Notch is sufficient to direct non-astrocytic progenitors toward astrocytic fate. We found that Prospero is a key effector of Notch in this process. Our data identify an instructive astrogenic program that acts as a binary switch to distinguish astrocytes from other glial cells.

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Activity-dependent regulation of astrocyte GAT levels during synaptogenesis

Cited by 128 publications

References 64 publications

Astrocytic glutamate transport regulates a Drosophila CNS synapse that lacks astrocyte ensheathment

Astrocytic glutamate transport regulates a Drosophila CNS synapse that lacks astrocyte ensheathment

DrosophilaCentral Nervous System Glia

Drosophila astrocytes cover specific territories of CNS neuropil and are instructed to differentiate by Prospero, a key effector of Notch

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