Cited by 322Ion Transport and Channel RegulationBarrier Structure and Function StudiesCerebrospinal fluid and hydrocephalus

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Brain Extracellular Space: The Final Frontier of Neuroscience

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Nicholson, Charles, Hrabětová, Sabina·2017·Biophysical Journal

DOI 10.1016/j.bpj.2017.06.052PMC PMC5700249

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Abstract

Brain extracellular space is the narrow microenvironment that surrounds every cell of the central nervous system. It contains a solution that closely resembles cerebrospinal fluid with the addition of extracellular matrix molecules. The space provides a reservoir for ions essential to the electrical activity of neurons and forms an intercellular chemical communication channel. Attempts to reveal the size and structure of the extracellular space using electron microscopy have had limited success; however, a biophysical approach based on diffusion of selected probe molecules has proved useful. A point-source paradigm, realized in the real-time iontophoresis method using tetramethylammonium, as well as earlier radiotracer methods, have shown that the extracellular space occupies ∼20% of brain tissue and small molecules have an effective diffusion coefficient that is two-fifths that in a free solution. Monte Carlo modeling indicates that geometrical constraints, including dead-space microdomains, contribute to the hindrance to diffusion. Imaging the spread of macromolecules shows them increasingly hindered as a function of size and suggests that the gaps between cells are predominantly ∼40 nm with wider local expansions that may represent dead-spaces. Diffusion measurements also characterize interactions of ions and proteins with the chondroitin and heparan sulfate components of the extracellular matrix; however, the many roles of the matrix are only starting to become apparent. The existence and magnitude of bulk flow and the so-called glymphatic system are topics of current interest and controversy. The extracellular space is an exciting area for research that will be propelled by emerging technologies.

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Authors: Nicholson, C., & Hrabětová, S.
Affiliations: SUNY Downstate Health Sciences University (US)
State University of New York (US)
Corresponding author: Nicholson, Charles
ORCID: Nicholson, Charles
Hrabětová, Sabina
Venue: Biophysical Journal
Publisher: Elsevier BV
Published: 2017-11
Volume: 113
Issue: 10
Pages: 2133-2142
ISSN: 0006-3495 (ISSN-L)
DOI: 10.1016/j.bpj.2017.06.052
PMC: PMC5700249
OpenAlex: W2737379596
Cited by: 321
References: 62
Citations by year: 2026: 28 · 2025: 40 · 2024: 35 · 2023: 51 · 2022: 44 · 2021: 41 · 2020: 31 · 2019: 28 · 2018: 20 · 2017: 3
FWCI: 2.10
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
Locations: Biophysical Journal (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) (R01-NS047557)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
Keywords: brain extracellular space, extracellular matrix, cerebrospinal fluid, Monte Carlo simulation, diffusion coefficient, macromolecular diffusion, intercellular spaces, chondroitin sulfate, heparan sulfate, bulk flow, glymphatic system
MeSH terms: Animals, Brain, Diffusion, Extracellular Space, Humans, Neurosciences, Molecular Imaging

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Brain Extracellular Space: The Final Frontier of Neuroscience

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