Spatial organization and dynamics of the extracellular space in the mouse retina

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10 Scopus citations


The extracellular space (ECS) plays an important role in the physiology of neural circuits. Despite our detailed understanding of the cellular architecture of the mammalian retina, little is known about the organization and dynamics of the retinal ECS. We developed an optical technique based on two-photon imaging of fluorescently labeled extracellular fluid to measure the ECS volume fraction (α) in the ex vivo retina of male and female mice. This method has high spatial resolution and can detect rapid changes in α evoked by osmotic challenge and neuronal activity. The measured ECS α varied dramatically in different layers of the adult mouse retina, with α equaling ∼0.050 in the ganglion cell layer, ∼0.122 in the inner plexiform layer (IPL), ∼0.025 in the inner nuclear layer (INL), ∼0.087 in the outer plexiform layer, and ∼0.026 in the outer nuclear layer (ONL). ECS α was significantly larger early in retinal development; α was 67% larger in the IPL and 100% larger in the INL in neonatal mice compared with adults. In adult retinas, light stimulation evoked rapid decreases in ECS α. Light-driven reductions in ECS α were largest in the IPL, where visual stimuli decreased α values ∼10%. These light-evoked decreases demonstrate that a physiological stimulus can lead to rapid changes in ECS α and indicate that activity-dependent regulation of extracellular space may contribute to visual processing in the retina. SIGNIFICANCE STATEMENT The volume fraction of the extracellular space (ECS α), that portion of CNS tissue occupied by interstitial space, influences the diffusion of neurotransmitters from the synaptic cleft and the volume transmission of transmitters. However, ECS α has never been measured in live retina, and little is known about how ECS α varies following physiological stimulation. Here we show that ECS α values vary dramatically between different retinal layers and decrease by 10% following light stimulation. ECS α differences within the retina will influence volume transmission and light-evoked α variations may modulate synaptic transmission and visual processing in the retina. Activity-dependent ECS α variations may represent a mechanism of synaptic modulation throughout the CNS.

Original languageEnglish (US)
Pages (from-to)7785-7794
Number of pages10
JournalJournal of Neuroscience
Issue number41
StatePublished - Oct 7 2020

Bibliographical note

Funding Information:
Received July 3, 2020; revised Aug. 24, 2020; accepted Aug. 31, 2020. Author contributions: S.P.K., A.R.N., and E.A.N. designed research; S.P.K., P.-P.C., A.R.N., and E.A.N. performed research; S.P.K., A.R.N., and E.A.N. analyzed data; S.P.K., A.R.N., and E.A.N. wrote the paper. This research was funded by National Institutes of Health Grants R01-EY-026514, R01-EY-026882, and P30-EY-011374 to E.A.N.; T90-DE-0227232 to S.P.K.; and T32-EY-025187 to A.R.N. We thank Charles Nicholson for helpful comments on an earlier version of the manuscript. The authors declare no competing financial interests. Correspondence should be addressed to Eric A. Newman at Copyright © 2020 the authors

Publisher Copyright:
Copyright © 2020 the authors.


  • Diffusion
  • Extracellular space
  • Glial cells
  • Light response
  • Retina
  • Volume fraction


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