Aquaporin: not so swell?

Fluid accumulation — or oedema — in the brain is a potentially life-threatening condition. It increases intracranial pressure, which can damage brain tissue and restrict blood supply. Thrane et al. now reveal molecular effects of brain oedema in astrocytes that could contribute to the pathophysiological outcome of the condition.

The authors injected mice with water to induce hypo-osmotic stress and consequently, brain oedema; they had previously shown that this causes astrocytes to swell. The authors first established whether aquaporin-4 (AQP4), a membrane protein that conducts water through the cell membrane, mediates astrocyte swelling. In acute cortical slices from mice lacking AQP4 (Aqp4^−/− mice) that were exposed to mild hypo-osmotic stress (20% reduction in osmolality), astrocyte swelling was greatly reduced compared with wild-type mice. In vivo two-photon imaging further revealed that mild hypo-osmotic stress increased Ca²⁺ spiking in astrocytes from wild-type animals but not from Aqp4^−/− mice. However, a more severe hypo-osmotic stress (30% reduction in osmolality) was capable of inducing both astrocyte swelling and Ca²⁺ spikes in Aqp4^−/− astrocytes, indicating that Ca²⁺ responses are triggered by AQP4-induced cell swelling and not directly by AQP4 itself.

As activation of purinergic receptors is known to trigger Ca²⁺ spikes in astrocytes, the authors assessed whether these receptors mediated the swelling-induced Ca²⁺ responses. They showed that wild-type astrocytes cultured in a hypo-osmotic medium released more ATP (which binds to purinergic P2 receptors) than cells cultured in an isotonic solution, whereas astrocytes from Aqp4^−/− mice showed no such response. Furthermore, adding P2 receptor antagonists to the culture medium delayed the onset of hypo-osmotic stress-induced Ca²⁺ responses in cortical slices from wild-type mice. Together, this indicates that P2 receptor activation mediates hypo-osmotic stress-induced, AQP4-dependent Ca²⁺ responses in astrocytes.

Thus, AQP4 mediates water influx in astrocytes under conditions of hypo-osmotic stress, and thereby initiates intracellular signalling events. This finding suggests that, in addition to increased intracranial pressure, potential cytotoxic downstream effects of signalling pathways activated in astrocytes may have a role in the pathophysiology of brain oedema.