Cellular mechanisms mediating activity-dependent extracellular space shrinkage in the retina

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Volume transmission plays an essential role in CNS function, with neurotransmitters released from synapses diffusing through the extracellular space (ECS) to distant sites. Changes in the ECS volume fraction (α) will influence the diffusion and the concentration of transmitters within the ECS. We have recently shown that neuronal activity evoked by physiological photic stimuli results in rapid decreases in ECS α as large as 10% in the retina. We now characterize the cellular mechanisms responsible for this ECS shrinkage. We find that block of inwardly rectifying K+ channels with Ba2+, inhibition of the Na+/K+/2Cl cotransporter with bumetanide, or block of AQP4 water channels with TGN-020 do not diminish the light-evoked ECS decrease. Inhibition of the Na+/HCO3 cotransporter by removing HCO3 from the superfusate, in contrast, reduces the light-evoked ECS decrease by 95.6%. Inhibition of the monocarboxylate transporter with alpha-cyano-4-hydroxycinnamate (4-CIN) also reduces the ECS shrinkage, but only by 32.5%. We tested whether the swelling of Müller cells, the principal glial cells of the retina, is responsible for the light-evoked ECS shrinkage. Light stimulation evoked a 6.3% increase in the volume of the fine processes of Müller cells. This volume increase was reduced by 97.1% when HCO3 was removed from the superfusate. We conclude that a large fraction of the activity-dependent decrease in ECS α is generated by the activation of the Na+/HCO3 cotransporter in Müller cells. The monocarboxylate transporter may also contribute to the response.

Original languageEnglish (US)
Pages (from-to)1927-1937
Number of pages11
Issue number10
StatePublished - Oct 2022

Bibliographical note

Funding Information:
Supported in part by National Institutes of Health Grants R01‐EY‐026514, R01‐EY‐026882, and P30‐EY‐011374 to E.A.N.

Publisher Copyright:
© 2022 The Authors. GLIA published by Wiley Periodicals LLC.


  • AQP4 channels
  • Müller cells
  • Na/HCO cotransporter
  • Na/K/2Cl cotransporter
  • extracellular space
  • glial cells
  • inwardly rectifying K channels
  • monocarboxylate transporter
  • retina

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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