Ischemic Brain Injury Leads to Brain Edema via Hyperthermia-Induced TRPV4 Activation.

Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain largely unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which male mouse brain slices were treated with oxygen-glucose deprivation (OGD) to mimic ischemia. We continuously measured the cross-sectional area of the brain slice for 150 min under macroscopic microscopy, finding that OGD induces swelling of brain slices. OGD-induced swelling was prevented by pharmacologically blocking or genetically knocking out the transient receptor potential vanilloid 4 (TRPV4), a member of the thermosensitive TRP channel family. Because TRPV4 is activated at around body temperature and its activation is enhanced by heating, we next elevated the temperature of the perfusate in the recording chamber, finding that hyperthermia induces swelling via TRPV4 activation. Furthermore, using the temperature-dependent fluorescence lifetime of a fluorescent-thermosensitive probe, we confirmed that OGD treatment increases the temperature of brain slices through the activation of glutamate receptors. Finally, we found that brain edema following traumatic brain injury was suppressed in TRPV4-deficient male mice in vivo Thus, our study proposes a novel mechanism: hyperthermia activates TRPV4 and induces brain edema after ischemia.SIGNIFICANCE STATEMENT Brain edema is characterized by an increase in net brain water content, which results in an increase in brain volume. Although brain edema is associated with a high fatality rate, the cellular and molecular processes of edema remain unclear. Here, we developed an in vitro model of ischemic stroke-induced edema in which mouse brain slices were treated with oxygen-glucose deprivation. Using this system, we showed that the increase in brain temperature and the following activation of the thermosensitive cation channel TRPV4 (transient receptor potential vanilloid 4) are involved in the pathology of edema. Finally, we confirmed that TRPV4 is involved in brain edema in vivo using TRPV4-deficient mice, concluding that hyperthermia activates TRPV4 and induces brain edema after ischemia.

Thermosensitive receptors in neural stem cells link stress-induced hyperthermia to impaired neurogenesis via microglial engulfment.

Social stress impairs hippocampal neurogenesis and causes psychiatric disorders such as depression. Recent studies have highlighted the significance of increased body temperature in stress responses; however, whether and how social stress­induced hyperthermia affects hippocampal neurogenesis remains unknown. Here, using transgenic mice in which the thermosensitive transient receptor potential vanilloid 4 (TRPV4) is conditionally knocked out in Nestin-expressing neural stem cells (NSCs), we found that social defeat stress (SDS)­induced hyperthermia activates TRPV4 in NSCs in the dentate gyrus and thereby impairs hippocampal neurogenesis. Specifically, SDS activated TRPV4 in NSCs and induced the externalization of phosphatidylserine in NSCs, which was recognized by the brain-resident macrophage, microglia, and promoted the microglial engulfment of NSCs. SDS-induced impairment of hippocampal neurogenesis was ameliorated by NSC-specific knockout of TRPV4 or pharmacological removal of microglia. Thus, this study reveals a previously unknown role of thermosensitive receptors expressed by NSCs in stress responses.