Decreased expression of the glial water channel aquaporin-4 in the intrahippocampal kainic acid model of epileptogenesis

Abstract

Recent evidence suggests that astrocytes may be a potential new target for the treatment of epilepsy. The glial water channel aquaporin-4 (AQP4) is expressed in astrocytes, and along with the inwardly-rectifying K+ channel Kir4.1 is thought to underlie the reuptake of H2O and K+ into glial cells during neural activity. Previous studies have demonstrated increased seizure duration and slowed potassium kinetics in AQP4−/− mice, and redistribution of AQP4 in hippocampal specimens from patients with chronic epilepsy. However, the regulation and role of AQP4 during epileptogenesis remain to be defined. In this study, we examined the expression of AQP4 and other glial molecules (GFAP, Kir4.1, glutamine synthetase) in the intrahippocampal kainic acid (KA) model of epilepsy and compared behavioral and histologic outcomes in wild-type mice vs. AQP4−/− mice. Marked and prolonged reduction in AQP4 immunoreactivity on both astrocytic fine processes and endfeet was observed following KA status epilepticus in multiple hippocampal layers. In addition, AQP4−/− mice had more spontaneous recurrent seizures than wild-type mice during the first week after KA SE as assessed by chronic video-EEG monitoring and blinded EEG analysis. While both genotypes exhibited similar reactive astrocytic changes, granule cell dispersion and CA1 pyramidal neuron loss, there were an increased number of fluorojade-positive cells early after KA SE in AQP4−/− mice. These results indicate a marked reduction of AQP4 following KA SE and suggest that dysregulation of water and potassium homeostasis occurs during early epileptogenesis. Restoration of astrocytic water and ion homeostasis may represent a novel therapeutic strategy.

Physiological Roles of Aquaporin-4 in Brain

“…Rodents that are exposed to kainic acid develop chronic seizures after a well-defined latent phase that is assumed to correspond to the premorbid state of MTLE patients. A loss of AQP4 and ␣-syntrophin from perivascular endfoot membranes was observed already in the latent phase, supporting the idea that these changes could be part of the pathogenic process leading to chronic seizures (3,82).…”

“…Loss of AQP4 from endfoot membranes is also found in epilepsy (33,82), traumatic brain injury (155), and a model of Alzheimer's disease (203). Generally, the polarized distribution of AQP4 is lost in reactive astrocytes (200).…”

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

“…Subcellular expression of AQP4 in brain astrocytes mimics that of Kir4.1, although AQP4 is more strongly expressed in perivascular regions (Nagelhus et al, 2004). However, down-regulation of AQP4 not accompanied by significant changes in Kir4.1 has been reported in hippocampal kainic acid mouse model of epileptogenesis (Lee et al, 2012). Furthermore, perivascular but not parenchymal loss of AQP4 has been observed in hippocampi of TLE patients (Eid et al, 2005).…”

Manganese and Neuroinflammation

“…Animals deficient in proteins important in either of these pathways is sufficient enough to cause or potentiate seizures. 76,77 Inflammatory-mediated pathways include enhancement of glutamatergic activation and potentiation of NMDA-induced currents, 25 increased release of gliotransmitters, and inhibition of astrocyte functions. 35,65,72,78 Implicated molecules include pro-inflammatory cytokines, nitric oxide, and arachadonic acid.…”