Force spectroscopy measurements show that cortical neurons exposed to excitotoxic agonists stiffen before showing evidence of bleb damage

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Journal titlePLoS ONE
Article numbere73499
Subjectcalcium ion; glutamic acid; hypotonic solution; myosin adenosine triphosphatase; n methyl dextro aspartic acid; sodium channel; sodium ion; spectrin; veratridine; water; actin myosin interaction; animal cell; animal experiment; animal model; animal tissue; article; atomic force microscopy based force spectroscopy; bilayer membrane; bleb damage; brain cell; brain injury; brain ischemia; calcium transport; cell damage; cell stiffening; cell swelling; cell volume; controlled study; elasticity; excitotoxicity; exposure; female; hydrostatic pressure; measurement; membrane damage; nerve cell necrosis; nonhuman; osmosis; positive feedback; rat; sodium transport; spectroscopy; traumatic brain injury; water transport
AbstractIn ischemic and traumatic brain injury, hyperactivated glutamate (N-methyl-D-aspartic acid, NMDA) and sodium (Nav) channels trigger excitotoxic neuron death. Na+, Ca++ and H2O influx into affected neurons elicits swelling (increased cell volume) and pathological blebbing (disassociation of the plasma membrane's bilayer from its spectrin-actomyosin matrix). Though usually conflated in injured tissue, cell swelling and blebbing are distinct processes. Around an injury core, salvageable neurons could be mildly swollen without yet having suffered the bleb-type membrane damage that, by rendering channels leaky and pumps dysfunctional, exacerbates the excitotoxic positive feedback spiral. Recognizing when neuronal inflation signifies non-lethal osmotic swelling versus blebbing should further efforts to salvage injury-penumbra neurons. To assess whether the mechanical properties of osmotically-swollen versus excitotoxically-blebbing neurons might be cytomechanically distinguishable, we measured cortical neuron elasticity (gauged via atomic force microscopy (AFM)-based force spectroscopy) upon brief exposure to hypotonicity or to excitotoxic agonists (glutamate and Nav channel activators, NMDA and veratridine). Though unperturbed by solution exchange per se, elasticity increased abruptly with hypotonicity, with NMDA and with veratridine. Neurons then invariably softened towards or below the pre-treatment level, sometimes starting before the washout. The initial channel-mediated stiffening bespeaks an abrupt elevation of hydrostatic pressure linked to NMDA or Nav channel-mediated ion/H2O fluxes, together with increased [Ca++]int-mediated submembrane actomyosin contractility. The subsequent softening to below-control levels is consistent with the onset of a lethal level of bleb damage. These findings indicate that dissection/identification of molecular events during the excitotoxic transition from stiff/swollen to soft/blebbing is warranted and should be feasible. © 2013 Zou et al.
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AffiliationNational Research Council Canada (NRC-CNRC); Measurement Science and Standards (MSS-SME); Human Health Therapeutics (HHT-TSH)
Peer reviewedYes
NPARC number21269829
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Record identifier666541e7-16a7-432b-a7d7-630cc8034238
Record created2013-12-13
Record modified2016-05-09
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