title: Activity-dependent regulation of astrocyte GAT levels during synaptogenesis.
abstract: Astrocytic uptake of GABA through GABA transporters (GATs) is an important mechanism regulating excitatory/inhibitory balance in the nervous system; however, mechanisms by which astrocytes regulate GAT levels are undefined. We found that at mid-pupal stages the Drosophila melanogaster CNS neuropil was devoid of astrocyte membranes and synapses. Astrocyte membranes subsequently infiltrated the neuropil coordinately with synaptogenesis, and astrocyte ablation reduced synapse numbers by half, indicating that Drosophila astrocytes are pro-synaptogenic. Shortly after synapses formed in earnest, GAT was upregulated in astrocytes. Ablation or silencing of GABAergic neurons or disruption of metabotropic GABA receptor 1 and 2 (GABA(B)R1/2) signaling in astrocytes led to a decrease in astrocytic GAT. Notably, developmental depletion of astrocytic GABA(B)R1/2 signaling suppressed mechanosensory-induced seizure activity in mutants with hyperexcitable neurons. These data reveal that astrocytes actively modulate GAT expression via metabotropic GABA receptor signaling and highlight the importance of precise regulation of astrocytic GAT in modulation of seizure activity.
authors.affiliation: 1] Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Allie K
authors.initials: AK
authors.lastname: Muthukumar
authors.affiliation: 1] Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Stork
authors.affiliation: 1] Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA. [2] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Freeman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D059330:GABAergic Neurons / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D010243:Paralysis / Q000209:etiology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010812:Physical Stimulation; D011108:Polymers; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C557617:GAL4 protein, Drosophila; D008164:Luminescent Proteins; D010455:Peptides; D011108:Polymers; D014157:Transcription Factors; C020749:GAT