title: Enhanced vulnerability to NMDA toxicity in sublethal traumatic neuronal injury in vitro.
abstract: Traumatic brain injury causes neuronal disruption and triggers secondary events leading to additional neuronal death. To study injuries triggered by secondary events, we exposed cultured cortical neurons to sublethal mechanical stretch, thus eliminating confounding death from primary trauma. Sublethally stretched neurons maintained cell membrane integrity, viability, and electrophysiological function. However, stretching induced in the cells a heightened vulnerability to subsequent challenges with L-glutamate or NMDA. This heightened vulnerability was specifically mediated by NMDA receptors (NMDARs), as stretched neurons did not become more vulnerable to either kainate toxicity or to that induced by the Ca(2+) ionophore A23187. Stretch-enhanced vulnerability to NMDA occurred independently of endogenous glutamate release, but required Ca(2+) and Na(+) influx through NMDARs. Stretch did not affect the electrophysiological properties of NMDARs nor excitatory synaptic activity, indicating that specificity of enhanced vulnerability to NMDA involves postsynaptic mechanisms downstream from NMDARs. To test whether this specificity requires physical interactions between NMDARs and cytoskeletal elements, we perturbed actin filaments and microtubules, both of which are linked to NMDARs. This had no effect on the stretch-induced vulnerability to NMDA, suggesting that sublethal stretch does not affect cell survival through the cytoskeleton. Our data illustrate that sublethal in vitro stretch injury triggers distinct signaling pathways that lead to secondary injury, rather than causing a generalized increase in vulnerability to secondary insults.
authors.affiliation: Toronto Western Hospital Research Institute, Toronto, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Arundine
authors.forename: Gopal K
authors.initials: GK
authors.lastname: Chopra
authors.forename: Andrew
authors.initials: A
authors.lastname: Wrong
authors.forename: Saobo
authors.initials: S
authors.lastname: Lei
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Aarts
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
authors.forename: Michael
authors.initials: M
authors.lastname: Tymianski
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000503:physiopathology; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity*; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D013314:Stress, Mechanical
chemical_list: D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate