Excitotoxicity is associated with stroke, brain trauma and neurodegenerative disorders. Focal swellings along dendrites called varicosities are a hallmark of acute excitotoxic neuronal injury. We previously reported that cultured mouse cortical neurons express the volume-sensitive outwardly rectifying (VSOR) chloride channel, which is involved in volume regulation after osmotic swelling. Here we studied a role of the VSOR chloride channel in excitotoxic neuronal injury in cultured mouse cortical neurons. The blockade of the VSOR chloride channel activity by NPPB (40 μM), phloretin (100 μM) or IAA-94 (1 mM) during excitotoxic stimulation inhibited varicosity formation and necrotic neuronal death. On the other hand, a GABAA receptor/chloride channel blocker, bicuculline (10 μM) or picrotoxin (100 μM), failed to inhibit neuronal necrosis induced by excitotoxicity. On-cell patch-clamp studies revealed robust VSOR chloride channel activity on varicosities during exposure to NMDA. These results suggest that the VSOR chloride channel is involved in aggravation of excitotoxicity by serving as the pathway for chloride influx, which induces varicosity formation and cell swelling leading to necrotic cell death. [J Physiol Sci. 2006;56 Suppl:S113]
