Loss of perivascular aquaporin 4 may underlie deficient water and K + homeostasis in the human epileptogenic hippocampus

Tore Eid, Tih Shih W Lee, Marion J. Thomas, Mahmood Amiry-Moghaddam, Lars P. Bjørnsen, Dennis D. Spencer, Peter C Agre, Ole P. Ottersen, Nihal C. De Lanerolle

Research output: Contribution to journalArticle

Abstract

An abnormal accumulation of extracellular K+ in the brain has been implicated in the generation of seizures in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis. Experimental studies have shown that clearance of extracellular K+ is compromised by removal of the perivascular pool of the water channel aquaporin 4 (AQP4), suggesting that an efficient clearance of K+ depends on a concomitant water flux through astrocyte membranes. Therefore, we hypothesized that loss of perivascular AQP4 might be involved in the pathogenesis of MTLE. Whereas Western blot analysis showed an overall increase in AQP4 levels in MTLE compared with non-MTLE hippocampi, quantitative ImmunoGold electron microscopy revealed that the density of AQP4 along the perivascular membrane domain of astrocytes was reduced by 44% in area CA1 of MTLE vs. non-MTLE hippocampi. There was no difference in the density of AQP4 on the astrocyte membrane facing the neuropil. Because anchoring of AQP4 to the perivascular astrocyte endfoot membrane depends on the dystrophin complex, the localization of the 71-kDa brain-specific isoform of dystrophin was assessed by immunohistochemistry. In non-MTLE hippocampus, dystrophin was preferentially localized near blood vessels. However, in the MTLE hippocampus, the perivascular dystrophin was absent in sclerotic areas, suggesting that the loss of perivascular AQP4 is secondary to a disruption of the dystrophin complex. We postulate that the loss of perivascular AQP4 in MTLE is likely to result in a perturbed flux of water through astrocytes leading to an impaired buffering of extracellular K+ and an increased propensity for seizures.

Original languageEnglish (US)
Pages (from-to)1193-1198
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number4
DOIs
StatePublished - Jan 25 2005

Fingerprint

Aquaporin 4
Temporal Lobe Epilepsy
Hippocampus
Homeostasis
Dystrophin
Water
Astrocytes
Membranes
Seizures
Aquaporins
Neuropil
Brain
Sclerosis
Blood Vessels
Electron Microscopy
Protein Isoforms
Western Blotting
Immunohistochemistry

Keywords

  • Astrocytes
  • Dystrophin
  • Epilepsy
  • Seizures

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Loss of perivascular aquaporin 4 may underlie deficient water and K + homeostasis in the human epileptogenic hippocampus. / Eid, Tore; Lee, Tih Shih W; Thomas, Marion J.; Amiry-Moghaddam, Mahmood; Bjørnsen, Lars P.; Spencer, Dennis D.; Agre, Peter C; Ottersen, Ole P.; De Lanerolle, Nihal C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 4, 25.01.2005, p. 1193-1198.

Research output: Contribution to journalArticle

Eid, Tore ; Lee, Tih Shih W ; Thomas, Marion J. ; Amiry-Moghaddam, Mahmood ; Bjørnsen, Lars P. ; Spencer, Dennis D. ; Agre, Peter C ; Ottersen, Ole P. ; De Lanerolle, Nihal C. / Loss of perivascular aquaporin 4 may underlie deficient water and K + homeostasis in the human epileptogenic hippocampus. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 4. pp. 1193-1198.
@article{b33c5530aaab4e708cec85a801e1ac5f,
title = "Loss of perivascular aquaporin 4 may underlie deficient water and K + homeostasis in the human epileptogenic hippocampus",
abstract = "An abnormal accumulation of extracellular K+ in the brain has been implicated in the generation of seizures in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis. Experimental studies have shown that clearance of extracellular K+ is compromised by removal of the perivascular pool of the water channel aquaporin 4 (AQP4), suggesting that an efficient clearance of K+ depends on a concomitant water flux through astrocyte membranes. Therefore, we hypothesized that loss of perivascular AQP4 might be involved in the pathogenesis of MTLE. Whereas Western blot analysis showed an overall increase in AQP4 levels in MTLE compared with non-MTLE hippocampi, quantitative ImmunoGold electron microscopy revealed that the density of AQP4 along the perivascular membrane domain of astrocytes was reduced by 44{\%} in area CA1 of MTLE vs. non-MTLE hippocampi. There was no difference in the density of AQP4 on the astrocyte membrane facing the neuropil. Because anchoring of AQP4 to the perivascular astrocyte endfoot membrane depends on the dystrophin complex, the localization of the 71-kDa brain-specific isoform of dystrophin was assessed by immunohistochemistry. In non-MTLE hippocampus, dystrophin was preferentially localized near blood vessels. However, in the MTLE hippocampus, the perivascular dystrophin was absent in sclerotic areas, suggesting that the loss of perivascular AQP4 is secondary to a disruption of the dystrophin complex. We postulate that the loss of perivascular AQP4 in MTLE is likely to result in a perturbed flux of water through astrocytes leading to an impaired buffering of extracellular K+ and an increased propensity for seizures.",
keywords = "Astrocytes, Dystrophin, Epilepsy, Seizures",
author = "Tore Eid and Lee, {Tih Shih W} and Thomas, {Marion J.} and Mahmood Amiry-Moghaddam and Bj{\o}rnsen, {Lars P.} and Spencer, {Dennis D.} and Agre, {Peter C} and Ottersen, {Ole P.} and {De Lanerolle}, {Nihal C.}",
year = "2005",
month = "1",
day = "25",
doi = "10.1073/pnas.0409308102",
language = "English (US)",
volume = "102",
pages = "1193--1198",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "4",

}

TY - JOUR

T1 - Loss of perivascular aquaporin 4 may underlie deficient water and K + homeostasis in the human epileptogenic hippocampus

AU - Eid, Tore

AU - Lee, Tih Shih W

AU - Thomas, Marion J.

AU - Amiry-Moghaddam, Mahmood

AU - Bjørnsen, Lars P.

AU - Spencer, Dennis D.

AU - Agre, Peter C

AU - Ottersen, Ole P.

AU - De Lanerolle, Nihal C.

PY - 2005/1/25

Y1 - 2005/1/25

N2 - An abnormal accumulation of extracellular K+ in the brain has been implicated in the generation of seizures in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis. Experimental studies have shown that clearance of extracellular K+ is compromised by removal of the perivascular pool of the water channel aquaporin 4 (AQP4), suggesting that an efficient clearance of K+ depends on a concomitant water flux through astrocyte membranes. Therefore, we hypothesized that loss of perivascular AQP4 might be involved in the pathogenesis of MTLE. Whereas Western blot analysis showed an overall increase in AQP4 levels in MTLE compared with non-MTLE hippocampi, quantitative ImmunoGold electron microscopy revealed that the density of AQP4 along the perivascular membrane domain of astrocytes was reduced by 44% in area CA1 of MTLE vs. non-MTLE hippocampi. There was no difference in the density of AQP4 on the astrocyte membrane facing the neuropil. Because anchoring of AQP4 to the perivascular astrocyte endfoot membrane depends on the dystrophin complex, the localization of the 71-kDa brain-specific isoform of dystrophin was assessed by immunohistochemistry. In non-MTLE hippocampus, dystrophin was preferentially localized near blood vessels. However, in the MTLE hippocampus, the perivascular dystrophin was absent in sclerotic areas, suggesting that the loss of perivascular AQP4 is secondary to a disruption of the dystrophin complex. We postulate that the loss of perivascular AQP4 in MTLE is likely to result in a perturbed flux of water through astrocytes leading to an impaired buffering of extracellular K+ and an increased propensity for seizures.

AB - An abnormal accumulation of extracellular K+ in the brain has been implicated in the generation of seizures in patients with mesial temporal lobe epilepsy (MTLE) and hippocampal sclerosis. Experimental studies have shown that clearance of extracellular K+ is compromised by removal of the perivascular pool of the water channel aquaporin 4 (AQP4), suggesting that an efficient clearance of K+ depends on a concomitant water flux through astrocyte membranes. Therefore, we hypothesized that loss of perivascular AQP4 might be involved in the pathogenesis of MTLE. Whereas Western blot analysis showed an overall increase in AQP4 levels in MTLE compared with non-MTLE hippocampi, quantitative ImmunoGold electron microscopy revealed that the density of AQP4 along the perivascular membrane domain of astrocytes was reduced by 44% in area CA1 of MTLE vs. non-MTLE hippocampi. There was no difference in the density of AQP4 on the astrocyte membrane facing the neuropil. Because anchoring of AQP4 to the perivascular astrocyte endfoot membrane depends on the dystrophin complex, the localization of the 71-kDa brain-specific isoform of dystrophin was assessed by immunohistochemistry. In non-MTLE hippocampus, dystrophin was preferentially localized near blood vessels. However, in the MTLE hippocampus, the perivascular dystrophin was absent in sclerotic areas, suggesting that the loss of perivascular AQP4 is secondary to a disruption of the dystrophin complex. We postulate that the loss of perivascular AQP4 in MTLE is likely to result in a perturbed flux of water through astrocytes leading to an impaired buffering of extracellular K+ and an increased propensity for seizures.

KW - Astrocytes

KW - Dystrophin

KW - Epilepsy

KW - Seizures

UR - http://www.scopus.com/inward/record.url?scp=12844282842&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=12844282842&partnerID=8YFLogxK

U2 - 10.1073/pnas.0409308102

DO - 10.1073/pnas.0409308102

M3 - Article

C2 - 15657133

AN - SCOPUS:12844282842

VL - 102

SP - 1193

EP - 1198

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 4

ER -