Aquaporin-4 regulates the velocity and frequency of cortical spreading depression in mice

Abstract

The astrocyte water channel aquaporin-4 (AQP4) regulates extracellular space (ECS) K+ concentration ([K+]e) and volume dynamics following neuronal activation. Here, we investigated how AQP4-mediated changes in [K+]e and ECS volume affect the velocity, frequency and amplitude of cortical spreading depression (CSD) depolarizations produced by surface KCl application in wild-type (AQP4+/+) and AQP4-deficient (AQP4−/−) mice. Contrary to initial expectations, both the velocity and frequency of CSD were significantly reduced in AQP4−/− mice when compared to AQP4+/+ mice, by 22% and 32%, respectively. Measurement of [K+]e with K+-selective microelectrodes demonstrated an increase to ~35 mM during spreading depolarizations in both AQP4+/+ and AQP4−/− mice, but the rates of [K+]e increase (3.5 vs. 1.5 mM/s) and reuptake (t1/2 33 vs. 61 s) were significantly reduced in AQP4−/− mice. ECS volume fraction measured by trimethylammonium iontophoresis was greatly reduced during depolarizations from 0.18 to 0.053 in AQP4+/+ mice, and 0.23 to 0.063 in AQP4−/− mice. Analysis of the experimental data using a mathematical model of CSD propagation suggested that the reduced velocity of CSD depolarizations in AQP4−/− mice was primarily a consequence of the slowed increase in [K+]e during neuronal depolarization. These results demonstrate that AQP4 effects on [K+]e and ECS volume dynamics accelerate CSD propagation.

TRPV4 channels contribute to calcium transients in astrocytes and neurons during peri‐infarct depolarizations in a stroke model

“…Of note, the osmotic stimuli necessary to evoke calcium transients downstream of AQP4 activation in earlier studies (Benfenati et al, ; Jo et al, ; Mola et al, ; Thrane et al, ) were considerably stronger than the ones induced in our study. Interestingly, it was recently shown that the DC potential amplitude (Thrane et al, ) and the threshold (Yao et al, ) of normoxic spreading depression are reduced in Aqp4–/– mice, indicating profound but incompletely understood differences between the mechanisms underlying spreading depolarizations in the healthy and ischemic brain. Finally, we did not detect significant differences in PID‐induced edema of astrocytes in Aqp4–/– compared with wildtype mice, indicating that aquaporins may not contribute to the level of cell swelling in astrocytes, similarly to what has been reported for neurons (Steffensen, Sword, Croom, Kirov, & MacAulay, ).…”

Susceptibility of the cerebral cortex to spreading depolarization in neurological disease states: The impact of aging

“…The effective involvement of astrocytic buffering in SD management was proven by deleting aquaporin-4 channels, or hindering glutamate clearance. As such, the genetic knock-out of aquaporin-4 channels in mice decreased the rate of the K + surge and K + reuptake with SD, in association with a slower rate of SD propagation, and lower SD frequency (Yao et al, 2015). On the other hand, EAAT2-mediated glutamate clearance hampered in the absence of the α2 subunit of the astrocytic Na + /K + ATPase was associated with the facilitation of SD initiation (Capuani et al, 2016).…”

Microglia alter the threshold of spreading depolarization and related potassium uptake in the mouse brain

“…Each K þ -selective microelectrode was calibrated in standard solutions of known K þ concentrations (1, 3, 5, 10, 30, 50 and 100 mM) (Figure 3(a)). 33 In each experiment, a K þ -sensitive microelectrode was lowered into the cortex, together with another microelectrode (outer tip diameter ¼ 20 mm) filled with 150 mM NaCl and 1 mM HEPES to serve as reference and acquire DC potential (<1Hz). An Ag/AgCl electrode implanted under the skin of the animal's neck was used as common ground.…”