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 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 EC(50) 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.