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.dystrophin ͉ epilepsy ͉ seizures ͉ astrocytes M esial temporal lobe epilepsy (MTLE) is one of the commonest forms of medically intractable epilepsies. MTLE is characterized by seizures that originate from mediobasal temporal lobe structures, particularly the hippocampus, and neurosurgical resection of the epileptogenic hippocampus is often used to treat this disorder. The resected, epileptogenic hippocampus in MTLE is typically indurated and atrophic and displays massive loss of neurons along with astroglial changes, particularly in areas CA1 and CA3 and the dentate hilus, a condition known as hippocampal (or Ammon's horn) sclerosis. Electrophysiological recordings from MTLE hippocampi have demonstrated that these hippocampi are hyperexcitable when compared with nonsclerotic hippocampi from patients with other types of temporal lobe epilepsy, such as mass associated temporal lobe epilepsy (patients with an extrahippocampal mass lesion) or paradoxical temporal lobe epilepsy (patients without a mass lesion and with seizures of unknown etiology). A fundamental question that remains to be resolved is why the MTLE hippocampus is hyperexcitable.Studies of MTLE patient hippocampi have shown that the K ϩ buffering capacity is diminished when compared with non-

Altered physiological brain variation in drug‐resistant epilepsy

“…Tissue samples of MTS have been shown to present a striking lack of peri‐vascular AQP4 water channels that mediates the glymphatic water clearance (Eid et al., 2005). The absence of AQP4 channels in MTS areas could lead to altered extracellular electrolyte concentrations that sensitizes neuronal tissue to seizures (Eid et al., 2005; Lundgaard et al., 2017; Marchi et al., 2007). …”

Astrocytes and Epilepsy

“…In sclerotic hippocampi the expression of AQP4 on the perivascular membrane of the astrocyte is reduced, whereas its expression remains unchanged on the membrane facing the neuropil, thus suggesting a probable decrease in the expulsion of water from the neuropil out to the blood vessel lumen. 25 …”

“…K ϩ and water are taken up by the astrocyte membrane facing the neuropil and pushed into the blood and CSF through the end foot membranes under conditions of high neuronal activity. 96 A loss of AQP4 from the perivascular membrane could impair water movements 25 and lead to increased extracellular concentrations of K ϩ , which can depolarize neurons in adjacent regions such as the subiculum. This buffering of K ϩ is probably performed by the GFAP positive subset of GluT-like astrocytes.…”

Nanoparticle transport across the blood brain barrier

“…11 Several evidences demonstrated that the epileptic seizures alter bloodbrain barrier (BBB) properties and permeability. 31,54,117 Particularly, a recently in vivo study demonstrated the dynamic changes of BBB permeability during epileptogenesis. The long-lasting increased permeability of the BBB indicated that it may contribute to increased excitability in the epileptogenic foci, leading to the progression of epilepsy and seizure development.…”