Enhancement of AMPA-mediated current after traumatic injury in cortical neurons

Overactivation of ionotropic glutamate receptors has been implicated in the pathophysiology of traumatic brain injury. Using an in vitro cell injury m odel, we examined the effects of stretch-induced traumatic injury on the AM PA subtype of ionotropic glutamate receptors in cultured neonatal cortical neurons. Recordings made using the whole-cell patch-clamp technique reveale d that a subpopulation of injured neurons exhibited an increased current in response to AMPA. The current-voltage relationship of these injured neuron s showed an increased slope conductance but no change in reversal potential compared with uninjured neurons. Additionally, the EC50 values of uninjure d and injured neurons were nearly identical. Thus, current potentiation was not caused by changes in the voltage-dependence, ion selectivity, or appar ent agonist affinity of the AMPA channel. AMPA-elicited current could also be fully inhibited by the application of selective AMPA receptor antagonist s, thereby excluding the possibility that current potentiation in injured n eurons was caused by the activation of other, nondesensitizing receptors. T he difference in current densities between control and injured neurons was abolished when AMPA receptor desensitization was inhibited by the coapplica tion of AMPA and cyclothiazide or by the use of kainate as an agonist, sugg esting that mechanical injury alters AMPA receptor desensitization. Reducti on of AMPA receptor desensitization after brain injury would be expected to further exacerbate the effects of increased postinjury extracellular gluta mate and contribute to trauma-related cell loss and dysfunctional synaptic information processing.