Workshop on Cortical Spreading Depression ( CSD ) and Related Neurological Phenomena

S (in alphabetic order by speaker surname) Speaker: David Andrew (Queen's University in Kingston, Ontario, Canada) Title: Spreading depolarization strength during ischemia determines higher brain susceptibility and lower brain resistance to acute injury. Abstract: Global ischemia caused by cardiac arrest, pulmonary failure, near-drowning or traumatic brain injury often damages the higher brain but not the brainstem, leading to a 'persistent vegetative state' where the patient is awake but not aware. Approximately 35,000 North Americans are held captive in this condition but how the lower brain is preferentially protected in these patients is not known. In the higher brain, ischemia elicits a profound ischemic depolarization (ID) causing neuronal dysfunction and vasoconstriction within minutes. Might brainstem nuclei generate less damaging ID and so be more resilient? Here we compared resistance to acute injury induced from simulated ischemia in 'higher' neurons (from neocortex, hippocampus, striatum ad thalamus) versus 'lower' hypothalamic and brainstem neurons in live slices from rat and mouse. Using whole-cell recordings from 165neurons from 12brain regions we show that during 1015 min of oxygen/glucose deprivation (OGD), higher projection neurons underwent strong and irreversibly damaging ID. In contrast, hypothalamic and brainstem neurons generated a weak and slow-onset ID, easily surviving the same insult. This differential injury to higher neurons was supported by Light Transmittance (LT) imaging and 2-photon microscopy. All of the above responses were mimicked by bath exposure to 100 J.lM ouabain which inhibits the Na+/K+ pump or to 1-10 nM palytoxin which converts the pump into an open cationic channel. Moreover unlike higher gray, lower gray matter could not generate a CSD-like event in response to elevated bath KCl. Thus spreading depolarizations promote higher, but not lower, brain shut-down during metabolic stress and we propose that this is evolutionarily adaptive, not simply pathological. But what determines shut-down propensity? The Na/K pump 1a3 isoform is expressed in higher proportion in the lower brain and functions more efficiently under ischemic conditions than Io I. We are currently investigating to what extent regional Na/K pump isoform expression influences susceptibility to spreading depolarization. Brisson CD, Hsieh Y-T, Kim D, Jin AY, Andrew RD (2014) Brainstem Neurons Survive the Identical Ischemic Stress That Kills Higher Neurons: Insight to the Persistent Vegetative State. PLoS ONE 9(5): e96585. doi:10.1371/journal. pone. 0096585.