Glutamate does not mediate acute neuronal damage after spreading depression induced by O-2/glucose deprivation in the hippocampal slice

This study argues that, in contrast to accepted excitotoxicity theory, O-2/ glucose deprivation damages neurons acutely by eliciting ischemic spreading depression (SD), a process not blocked by glutamate antagonists. In live r at hippocampal slices, the initiation, propagation. and resolution of SD ca n be imaged by monitoring wide-band changes in light transmittance (i.e., i ntrinsic optical signals). Oxygen/glucose deprivation for 10 minutes at 37. 5 degrees C evokes a propagating wave of elevated light transmittance acros s the slice, representing the SD front. Within minutes. CA1 neurons in regi ons undergoing SD display irreversible damage in the form of field potentia l inactivation, swollen cell bodies, and extensively beaded dendrites. the latter revealed by single-cell injection of lucifer yellow. Importantly, gl utamate receptor antagonists do not block SD induced by O-2/glucose depriva tion, nor do they prevent the resultant dendritic beading of CA1 neurons. H owever, CA1 neurons are spared if SD is suppressed by reducing the temperat ure to 35 degrees C during O-2/glucose deprivation. This supports previous electrophysiologic evidence in vivo that SD during ischemia promotes acute neuronal damage and that glutamate antagonists are not protective of the me tabolically stressed tissue. The authors propose that the inhibition of isc hemic SD should be targeted as an important therapeutic strategy against st roke damage.