Delayed K+Clearance Associated with Aquaporin-4 Mislocalization: Phenotypic Defects in Brains of α-Syntrophin-Null Mice

Recovery from neuronal activation requires rapid clearance of potassium ions (K+)and restoration of osmotic equilibrium. The predominant water channel protein in brain, aquaporin-4 (AQP4), is concentrated in the astrocyte end-feet membranes adjacent to blood vessels in neocortex and cerebellum by association with α-syntrophin protein. Although AQP4 has been implicated in the pathogenesis of brain edema, its functions in normal brain physiology are uncertain. In this study, we used immunogold electron microscopy to compare hippocampus of WT and α-syntrophin-null mice (α-Syn-/-). We found that (\lbrack K^+\rbrack_o)$from the target zones of Schaffer collaterals and perforant path were obtained after 5-, 10-, and 20-Hz orthodromic stimulations. K+clearance was prolonged up to 2-fold in α-Syn-/-mice compared with WT mice. Furthermore, the intensity of hyperthermia-induced epileptic seizures was increased in approximately half of the α-Syn-/-mice. These studies lead us to propose that water flux through perivascular AQP4 is needed to sustain efficient removal of K+after neuronal activation.