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Cited by 64Barrier Structure and Function StudiesConnexins and lens biologyIon Transport and Channel Regulation

Albumin is taken up by hippocampal NG2 cells and astrocytes and decreases gap junction coupling

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Braganza, Oliver, Bedner, Peter, Hüttmann, Kerstin, von Staden, Elena, Friedman, Alon, Seifert, Gerald, Steinhäuser, Christian·2012·Epilepsia
DOI 10.1111/j.1528-1167.2012.03665.xPMC PMC3651829
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Abstract

Summary: Purpose: Dysfunction of the blood–brain barrier (BBB) and albumin extravasation have been suggested to play a role in the etiology of human epilepsy. In this context, dysfunction of glial cells attracts increasing attention. Our study was aimed to analyze in the hippocampus (1) which cell types internalize albumin injected into the lateral ventricle in vivo, (2) whether internalization into astrocytes impacts their coupling and expression of connexin 43 (Cx43), and (3) whether expression of Kir4.1, the predominating astrocytic K+ channel subunit, is altered by albumin. Methods: The patch‐clamp method was combined with single cell tracer filling to investigate electrophysiologic properties and gap junction coupling (GJC). For cell identification, mice with cell type–specific expression of a fluorescent protein (NG2kiEYFP mice) and immunohistochemistry were employed. Semiquantitative real time polymerase chain reaction (RT‐PCR) allowed analysis of Kir4.1 and Cx43 transcript levels. Key Findings: We show that fluorescently labeled albumin is taken up by astrocytes, NG2 cells, and neurons, with NG2 cells standing out in terms of the quantity of uptake. Within 5 days postinjection (dpi), intracellular albumin accumulation was largely reduced suggesting rapid degradation. Electrophysiologic analysis of astrocytes and NG2 cells revealed no changes in their membrane properties at either time point. However, astrocytic GJC was significantly decreased at 1 dpi but returned to control levels within 5 dpi. We found no changes in hippocampal Cx43 transcript expression, suggesting that other mechanisms account for the observed changes in coupling. Kir4.1 mRNA was regulated oppositely in the CA1 stratum radiatum, with a strong increase at 1 dpi followed by a decrease at 5 dpi. Significance: The present study demonstrates that extravasal albumin in the hippocampus induces rapid changes of astrocyte function, which can be expected to impair ion and transmitter homeostasis and contribute to hyperactivity and epileptogenesis. Therefore, astrocytes may represent alternative targets for antiepileptic therapeutic approaches.

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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 [76]

    The Key Findings report albumin uptake by astrocytes, NG2-positive cells, and neurons. The Results describe a few albumin-positive cells with electrical patterns resembling microglia, but do not establish their identity; the paper does not report albumin uptake by brain macrophages. No page numbers are available in our copy. (LLM, conf=0.87)

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Research works printed but not linked: 36

  1. Alonso G NG2 proteoglycan-expressing cells of the adult rat brain: possible involvement in the formation of glial scar astrocytes following stab wound Glia 2005 49 318 338 15494983
  2. Bergles DE Jabs R Steinhäuser C Neuron-glia synapses in the brain Brain Res Rev 2010 63 130 137 20018210 PMC2862892
  3. Bordey A Sontheimer H Postnatal development of ionic currents in rat hippocampal astrocytes in situ J Neurophysiol 1997 78 461 477 9242294
  4. Cacheaux LP Ivens S David Y Lakhter AJ Bar-Klain G Shapira M Heinemann U Friedman A Kaufer D Transcriptome profiling reveals TGF-ß signaling involvement in epileptogenesis J Neurosci 2009 29 8927 8935 19605630 PMC2875073
  5. Danbolt NC Glutamate uptake Prog Neurobiol 2001 65 1 105 11369436
  6. Friedman A Kaufer D Heinemann U Blood–brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy Epilepsy Res 2009 85 142 149 19362806 PMC3615244
  7. Hinterkeuser S Schröder W Hager G Seifert G Blümcke I Elger CE Schramm J Steinhäuser C Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances Eur J Neurosci 2000 12 2087 2096 10886348
  8. Hsu MS Seldin M Lee DJ Seifert G Steinhäuser C Binder DK Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus Neuroscience 2011 178 21 32 21256195 PMC3049969
  9. Ivens S Kaufer D Flores LP Bechmann I Zumsteg D Tomkins O Seiffert E Heinemann U Friedman A TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis Brain 2007 130 535 547 17121744
  10. Jabs R Pivneva T Hüttmann K Wyczynski A Nolte C Kettenmann H Steinhäuser C Synaptic transmission onto hippocampal glial cells with hGFAP promoter activity J Cell Sci 2005 118 3791 3803 16076898
  11. Karram K Goebbels S Schwab M Jennissen K Seifert G Steinhäuser C Nave KA Trotter J NG2-expressing cells in the nervous system revealed by the NG2-EYFP-knockin mouse Genesis 2008 46 743 757 18924152
  12. Kivi A Lehmann TN Kovacs R Eilers A Jauch R Meencke HJ Von Deimling A Heinemann U Gabriel S Effects of barium on stimulus-induced rises of [K+]o in human epileptic non-sclerotic and sclerotic hippocampal area CA1 Eur J Neurosci 2000 12 2039 2048 10886343
  13. Kofuji P Newman EA Potassium buffering in the central nervous system Neuroscience 2004 129 1045 1056 15561419 PMC2322935
  14. Komitova M Serwanski DR Lu QR Nishiyama A NG2 cells are not a major source of reactive astrocytes after neocortical stab wound injury Glia 2011 59 800 809 21351161 PMC3560299
  15. Kressin K Kuprijanova E Jabs R Seifert G Steinh user C Developmental regulation of Na+ and K+ conductances in glial cells of mouse hippocampal brain slices Glia 1995 15 173 187 8567069
  16. Matthias K Kirchhoff F Seifert G Hüttmann K Matyash M Kettenmann H Steinhäuser C Segregated expression of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus J Neurosci 2003 23 1750 1758 12629179 PMC6741945
  17. Matyash V Kettenmann H Heterogeneity in astrocyte morphology and physiology Brain Res Rev 2010 63 2 10 20005253
  18. Nishiyama A Komitova M Suzuki R Zhu X Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity Nat Rev Neurosci 2009 10 9 22 19096367
  19. Oby E Janigro D The blood–brain barrier and epilepsy Epilepsia 2006 47 1761 1774 17116015
  20. Olsen M Sontheimer H Functional implications for Kir4.1 channels in glial biology: from K+ buffering to cell differentiation J Neurochem 2008 107 589 601 18691387 PMC2581639
  21. Ozerdem U Grako KA Hlin-Huppe K Monosov E Stallcup WB NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis Dev Dyn 2001 222 218 227 11668599
  22. Peterson DA Quantitative histology using confocal microscopy: implementation of unbiased stereology procedures Methods 1999 18 493 507 10491280
  23. Raabe A Schmitz AK Pernhorst K Grote A von der Brelie C Urbach H Friedman A Becker AJ Elger CE Niehusmann P Cliniconeuropathologic correlations show astroglial albumin storage as a common factor in epileptogenic vascular lesions Epilepsia 2012 53 539 548 22372630 PMC3669690
  24. Rhodes KE Raivich G Fawcett JW The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines Neuroscience 2006 140 87 100 16631314
  25. Rouach N Koulakoff A Abudara V Willecke K Giaume C Astroglial metabolic networks sustain hippocampal synaptic transmission Science 2008 322 1551 1555 19056987
  26. Schröder W Hinterkeuser S Seifert G Schramm J Jabs R Wilkin GP Steinhäuser C Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy Epilepsia 2000 41 S181 S184 10999541
  27. Schröder W Seifert G Hüttmann K Hinterkeuser S Steinhäuser C AMPA receptor-mediated modulation of inward rectifier K+ channels in astrocytes of mouse hippocampus Mol Cell Neurosci 2002 19 447 458 11906215
  28. Seifert G Schilling K Steinhäuser C Astrocyte dysfunction in neurological disorders: a molecular perspective Nat Rev Neurosci 2006 7 194 206 16495941
  29. Seifert G Hüttmann K Binder DK Hartmann C Wyczynski A Neusch C Steinh user C Analysis of astroglial K+ channel expression in the developing hippocampus reveals a predominant role of the Kir4.1 subunit J Neurosci 2009 29 7474 7488 19515915 PMC6665420
  30. Seifert G Carmignoto G Steinhäuser C Astrocyte dysfunction in epilepsy Brain Res Rev 2010 63 212 221 19883685
  31. Seiffert E Dreier JP Ivens S Bechmann I Tomkins O Heinemann U Friedman A Lasting blood–brain barrier disruption induces epileptic focus in the rat somatosensory cortex J Neurosci 2004 24 7829 7836 15356194 PMC6729929
  32. Solan JL Lampe PD Connexin43 phosphorylation: structural changes and biological effects Biochem J 2009 419 261 272 19309313 PMC2669545
  33. Tomkins O Friedman O Ivens S Reiffurth C Major S Dreier JP Heinemann U Friedman A Blood–brain barrier disruption results in delayed functional and structural alterations in the rat neocortex Neurobiol Dis 2007 25 367 377 17188501
  34. Van Vliet EA da Costa AS Redeker S van Schaik R Aronica E Gorter JA Blood–brain barrier leakage may lead to progression of temporal lobe epilepsy Brain 2007 130 521 534 17124188
  35. Wallraff A Odermatt B Willecke K Steinhäuser C Distinct types of astroglial cells in the hippocampus differ in gap junction coupling Glia 2004 48 36 43 15326613
  36. Wallraff A Köhling R Heinemann U Theis M Willecke K Steinhäuser C The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus J Neurosci 2006 26 5438 5447 16707796 PMC6675300

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Authors
Braganza, O., Bedner, P., Hüttmann, K., von Staden, E., Friedman, A., Seifert, G., & Steinhäuser, C.
Affiliations
  • University of Bonn (DE)
  • Ben-Gurion University of the Negev (IL)
Corresponding author
Steinhäuser, Christian
ORCID
Venue
Epilepsia
Publisher
Wiley
Published
2012-09-11
Volume
53
Issue
11
Pages
1898-1906
ISSN
  • 0013-9580 (ISSN-L)
  • 1528-1167
DOI
10.1111/j.1528-1167.2012.03665.x
PMC
PMC3651829
OpenAlex
W1756495314
Cited by
64
References
2
Citations by year
2025: 3 · 2024: 7 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 6 · 2013: 1
FWCI
2.09
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Epilepsia (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • European Commission (202167)
  • Deutsche Forschungsgemeinschaft (SFB TR 3, FP7-202167, SPP-1172)
  • National Institute of Neurological Disorders and Stroke (R01NS066005)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
albumin uptake, hippocampus, oligodendrocyte precursor cells, astrocytes, electrical coupling, connexin 43, Kir4.1, blood-brain barrier dysfunction, epilepsy, epileptogenesis, albumin extravasation, CA1 stratum radiatum, ion homeostasis
MeSH terms
Animals, Astrocytes, Fluorescent Dyes, Hippocampus, Injections, Intraventricular, Mice, Inbred C57BL, Mice, Transgenic, Serum Albumin, Gap Junctions, Mice

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