The Journal of Neuroscience, September 1, 1999, 19(17):7367-7374
Enhancement of AMPA-Mediated Current after Traumatic Injury in
Cortical Neurons
Paulette B.
Goforth,
Earl F.
Ellis, and
Leslie S.
Satin
Departments of Pharmacology/Toxicology and Physiology, Medical
College of Virginia, Virginia Commonwealth University, Richmond,
Virginia 23298
Overactivation of ionotropic glutamate receptors has been
implicated in the pathophysiology of traumatic brain injury.
Using an in vitro cell injury model, we examined the
effects of stretch-induced traumatic injury on the AMPA subtype of
ionotropic glutamate receptors in cultured neonatal cortical neurons.
Recordings made using the whole-cell patch-clamp technique revealed
that a subpopulation of injured neurons exhibited an increased current
in response to AMPA. The current-voltage relationship of these injured
neurons showed an increased slope conductance but no change in reversal potential compared with uninjured neurons. Additionally, the
EC50 values of uninjured and injured neurons were nearly
identical. Thus, current potentiation was not caused by changes
in the voltage-dependence, ion selectivity, or apparent agonist
affinity of the AMPA channel. AMPA-elicited current could also be fully
inhibited by the application of selective AMPA receptor antagonists,
thereby excluding the possibility that current potentiation in injured
neurons was caused by the activation of other, nondesensitizing
receptors. The difference in current densities between control and
injured neurons was abolished when AMPA receptor desensitization was
inhibited by the coapplication of AMPA and cyclothiazide or by the use
of kainate as an agonist, suggesting that mechanical injury alters AMPA
receptor desensitization. Reduction of AMPA receptor desensitization
after brain injury would be expected to further exacerbate the effects
of increased postinjury extracellular glutamate and contribute to
trauma-related cell loss and dysfunctional synaptic information processing.
Key words:
glutamate; traumatic brain injury; AMPA receptor; desensitization; excitotoxicity; cortex
Copyright © 1999 Society for Neuroscience 0270-6474/99/19177367-08$05.00/0
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