Activity-dependent regulation of astrocyte GAT levels during synaptogenesis

Nat Neurosci. 2014 Oct;17(10):1340-50. doi: 10.1038/nn.3791. Epub 2014 Aug 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Astrocytes / metabolism*
  • Astrocytes / ultrastructure
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • GABAergic Neurons / physiology
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Neurogenesis / physiology*
  • Neurons / physiology
  • Neurons / ultrastructure
  • Paralysis / etiology
  • Peptides / genetics
  • Peptides / metabolism*
  • Physical Stimulation
  • Polymers
  • Synapses / metabolism*
  • Synapses / ultrastructure
  • Temperature
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Drosophila Proteins
  • GAL4 protein, Drosophila
  • Luminescent Proteins
  • Peptides
  • Polymers
  • Transcription Factors
  • GAT