Bidirectional regulation of glial potassium buffering - glioprotection versus neuroprotection

Elife. 2021 Mar 1;10:e62606. doi: 10.7554/eLife.62606.

Abstract

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A salt inducible kinase 3 (SIK3)-regulated gene expression program controls the glial capacity to buffer K+ and water in Drosophila, however upstream regulatory mechanisms are unknown. Here, we identify an octopaminergic circuit linking neuronal activity to glial ion and water buffering. Under basal conditions, octopamine functions through the inhibitory octopaminergic G-protein-coupled receptor (GPCR) OctβR to upregulate glial buffering capacity, while under pathological K+ stress, octopamine signals through the stimulatory octopaminergic GPCR OAMB1 to downregulate the glial buffering program. Failure to downregulate this program leads to intracellular glia swelling and stress signaling, suggesting that turning down this pathway is glioprotective. In the eag shaker Drosophila seizure model, the SIK3-mediated buffering pathway is inactivated. Reactivation of the glial buffering program dramatically suppresses neuronal hyperactivity, seizures, and shortened life span in this mutant. These findings highlight the therapeutic potential of a glial-centric therapeutic strategy for diseases of hyperexcitability.

Keywords: D. melanogaster; HDAC4; astrocytes; axon; cell biology; cell volume regulation; epilepsy; neuroscience; transporter.

Publication types

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

MeSH terms

  • Animals
  • Drosophila melanogaster / genetics*
  • Gene Expression Regulation
  • Larva
  • Neuroglia / metabolism*
  • Neuroprotection
  • Octopamine
  • Potassium / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Seizures / genetics
  • Seizures / metabolism*
  • Water / metabolism

Substances

  • Receptors, G-Protein-Coupled
  • Water
  • Octopamine
  • Protein Serine-Threonine Kinases
  • Potassium