SPREADING DEPRESSION DETERMINES ACUTE CELLULAR-DAMAGE IN THE HIPPOCAMPAL SLICE DURING OXYGEN GLUCOSE DEPRIVATION/

During ischaemia neurons depolarize and release the neurotransmitter L -glutamate, which accumulates extracellularly and binds to postsynapti c receptors. This initiates a sequence of events thought to culminate in immediate and delayed neuronal death. However, there is growing evi dence that during ischaemia the development of spreading depression (S D) can be an important determinant of the degree and extent of ischaem ic damage. in contrast, SD without metabolic compromise (as occurs in migraine aura) causes no discernible damage to brain tissue. SD is a p rofound depolarization of neurons and glia that propagates like a wave across brain tissue. Brain cell swelling, an early event of both the excitotoxic process and of SD, can be assessed by imaging associated i ntrinsic optical signals (IOSs). We demonstrate here that IOS imaging clearly demarcates the ignition site and migration of SD across the su bmerged hippocampal slice of the rat. If SD is induced by elevating [K +](o), the tissue fully recovers, but in slices that are metabolically compromised at 37.5 degrees C by oxygen/glucose deprivation (OGD) or by ouabain exposure, cellular damage develops only where SD has propag ated. Specifically, the evoked CA1 field potential is permanently lost , the cell bodies of involved neurons swell and their dendritic region s increase in opacity. In contrast to OGD, bath application of L-gluta mate (6-10 mM) at 37.5 degrees C evokes a non-propagating LT increase in CA1 that reverses without obvious cellular damage. Moreover, applic ation of 2-20 mM glutamate or various glutamate agonists fail to evoke SD in the submerged hippocampal slice. We propose that SD and OGD tog ether (but not alone) constitute a 'one-two punch', causing acute neur onal death in the slice that is not replicated by elevated glutamate. These findings support the proposal that SD generation during stroke p romotes and extends acute ischaemic damage.