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Mechanisms of Spreading Depolarizations and Contributions to Acute Brain Injury

Weekly Seminar
Who Should Attend: 


Guest Speaker
William C. Shuttleworth, Ph.D.
Regents’ Professor
Department of Neurosciences
Director, Center for Brain Recovery and Repair
Associate Director, Clinical and Translational Science Center
University of New Mexico Health Sciences Center Albuquerque, NM

Research Abstract

This talk focusses on slowly-propagating waves of profound and long-lasting depolarization, termed “spreading depolarization” (SD). SDs are quite unlike neuronal depolarizations observed in normal synaptic communication, and are also fundamentally different from seizures. The most important differences are the very slow propagation rates (~2-4mm/min), large amplitudes and the extraordinarily long periods of sustained depolarization (measured in minutes, rather than milliseconds) as individual waves sweep through a volume of brain tissue. The events are carried by extracellular accumulation of glutamate and/or K+, and result in large amounts of ATP being expended to restore ionic gradients after SD. When they occur in otherwise healthy brain, SDs do not cause damage, as there is usually sufficient supply of metabolic substrates to restore membrane potentials. However, there is now very strong evidence that when SDs occur in injured brain, they are a key contributor to injury expansion. Breakthrough work in the last decade has revealed that SDs are a common feature after acute brain injury in humans and (as predicted from prior rodent studies) appear to be causative events, underlying stepwise expansion of injury in the days following injury. The talk will include work form our lab describing mechanisms underlying neuronal vulnerability and protection from SDs, and work with clinical collaborators testing interventions in the ICU.

William C. Shuttleworth, Ph.D. Figure

Prolonged NMDAR activation contributes to neuronal injury in metabolically compromised neurons
Energy metabolism of single neurons was partially inhibited by brief dialysis with sodium azide-containing internal solution, and Ca2+ responses during spreading depolarization (SD) were then evaluated. A, raw image of Fura-6F fluorescence (380 nm excitation, left panel, scale bar:20 μm) and selected pseudo-coloured images representing intracellular Ca2+ levels at times indicated in minutes. Calculated Ca2+ concentrations from this neuron are shown in B (soma values in blue, dendrite values determined from region indicated by arrows are in red). Note that even thought there was an initial transient recovery of somatic Ca2+ responses after the initial peak, sustained Ca2+ deregulation rapidly developed throughout the neuron after SD. C and D, same as described above for A and B, with exception that DL-AP5 was applied locally to this selectively vulnerable neuron after the passage of SD. Note the prompt recovery of Ca2+ levels throughout the neuron. E, population data from control (black traces, n = 5) and DL-AP5-treated preparations (red traces, n = 5), showing the effectiveness of delayed DL-AP5 applications on neuronal Ca2+ overload, measured in somatic compartments of sodium azide-loaded neurons Arrowhead indicates SD onset and the horizontal bar indicated the duration of vehicle (ACSF) or DL-AP5 pressure pulse applications.


Aiba I, Shuttleworth CW.
Sustained NMDA receptor activation by spreading depolarizations can initiate excitotoxic injury in metabolically compromised neurons.
J Physiol. 2012 Nov 15;590(22):5877-93. doi: 10.1113/jphysiol.2012.234476. Epub 2012 Aug 20.
Lindquist BE, Shuttleworth CW.
Evidence that adenosine contributes to Leao's spreading depression in vivo.
J Cereb Blood Flow Metab. 2017 May;37(5):1656-1669. doi: 10.1177/0271678X16650696. Epub 2016 Jan 1.
Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, Andrew RD, Boutelle MG, Brennan KC, Carlson AP, Dahlem MA, Drenckhahn C, Dohmen C, Fabricius M, Farkas E, Feuerstein D, Graf R, Helbok R, Lauritzen M, Major S, Oliveira-Ferreira AI, Richter F, Rosenthal ES, Sakowitz OW, Sánchez-Porras R, Santos E, Schöll M, Strong AJ, Urbach A, Westover MB, Winkler MK, Witte OW, Woitzik J, Dreier JP.
The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.
J Cereb Blood Flow Metab. 2017 May;37(5):1571-1594. doi: 10.1177/0271678X16654495. Epub 2016 Jan 1.


Tuesday, September 12, 2017 - 12:30pm


Burke Medical Research Institute
785 Mamaroneck Avenue
White Plains, NY 10605
United States
Conference Room: 
Billings Building – Rosedale

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