TGF- receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis
Open accessAbstract
It has long been recognized that insults to the cerebral cortex, such as trauma, ischaemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the mechanisms underlying these processes are not known. In this study, we reveal a novel mechanism for epileptogenesis in the injured brain. We used focal neocortical, long-lasting BBB disruption or direct exposure to serum albumin in rats (51 and 13 animals, respectively, and 26 controls) as well as albumin exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed hypersynchronous propagating epileptiform field potentials when examined 5-49 days after treatment, but only 14% (n = 71) of control slices showed similar responses. We demonstrate that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes, which is mediated by transforming growth factor beta receptors (TGF-betaRs). This uptake is followed by down regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent increased accumulation of extracellular potassium, resulting in facilitated N-methyl-d-aspartate-receptor-mediated neuronal hyperexcitability and eventually epileptiform activity. Blocking TGF-betaR in vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% (n = 41 slices, P < 0.05). We propose that the above-described cascade of events following common brain insults leads to brain dysfunction and eventually epilepsy and suggest TGF-betaRs as a possible therapeutic target.
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Brain macrophages, microglia, astrocytes, neurons, and NG2-positive cells can take up albumin.
“Given that brain macrophages, microglia, astrocytes, neurons, and neuronglial antigen 2-positive cells can take up albumin (76, 286, 355)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [286]
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- Authors
- Ivens, S., Kaufer, D., Flores, L. P., Bechmann, I., Zumsteg, D., Tomkins, O., Seiffert, E., Heinemann, U., & Friedman, A.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- University of California, Berkeley (US)
- University of Toronto (CA)
- Ben-Gurion University of the Negev (IL)
- Corresponding author
- Ivens, S.
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-02-01
- Volume
- 130
- Issue
- 2
- Pages
- 535-547
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2078412655
- Cited by
- 567
- References
- 2
- Citations by year
- 2026: 31 · 2025: 21 · 2024: 30 · 2023: 33 · 2022: 24 · 2021: 24 · 2020: 25 · 2019: 29 · 2018: 28 · 2017: 28 · 2016: 32 · 2015: 24 · 2014: 41 · 2013: 32 · 2012: 46
- FWCI
- 12.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Brain (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- German-Israeli Foundation for Scientific Research and Development
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- epileptogenesis, serum albumin, astrocytes, TGF-beta receptor, blood-brain barrier disruption, Kir4.1 potassium channel, epileptiform activity, neurovascular integrity, brain injury, therapeutic target
- MeSH terms
- Kcnj10 Channel, Animals, Astrocytes, Blood-Brain Barrier, Disease Models, Animal, Electroencephalography, Epilepsy, Magnetic Resonance Imaging, Neurons, Potassium, Serum Albumin, Down-Regulation, Rats, Wistar, Receptors, Transforming Growth Factor beta, Neocortex, Potassium Channels, Inwardly Rectifying, Tissue Culture Techniques, Rats
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