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.
authors.affiliation: Department of Neurosurgery, Laboratory Medicine, and Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA. tore.eid@yale.edu
authors.forename: Tore
authors.initials: T
authors.lastname: Eid
authors.forename: Tih-Shih W
authors.initials: TS
authors.lastname: Lee
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Thomas
authors.forename: Mahmood
authors.initials: M
authors.lastname: Amiry-Moghaddam
authors.forename: Lars P
authors.initials: LP
authors.lastname: Bjørnsen
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Spencer
authors.forename: Peter
authors.initials: P
authors.lastname: Agre
authors.forename: Ole P
authors.initials: OP
authors.lastname: Ottersen
authors.forename: Nihal C
authors.initials: NC
authors.lastname: de Lanerolle
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D051401:Aquaporin 4; D020346:Aquaporins / Q000032:analysis*; D001253:Astrocytes / Q000737:chemistry; D001834:Body Water / Q000378:metabolism*; D002648:Child; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D011188:Potassium / Q000378:metabolism*
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; D020346:Aquaporins; D011188:Potassium