Progressive loss of phasic, but not tonic, GABAA receptor-mediated inhibition in dentate granule cells in a model of post-traumatic epilepsy in rats.

Traumatic brain injury (TBI) is a risk factor for the development of epilepsy, which can occur months to years after the insult. The hippocampus is particularly vulnerable to the pathophysiological effects of TBI. Here, we determined whether there are long-term changes in inhibition in the den- tate gyrus that could contribute to the progressive suscepti- bility to seizures after TBI. We used severe lateral-fluid per- cussion brain injury to induce TBI in rats. In this model, spontaneous seizure activity, which involves the hippocam- pus, appears after a long latent period, resembling the human condition. We demonstrate that synaptic GABAA receptor- mediated inhibition is profoundly reduced in ipsilateral den- tate granule cells 1 month after TBI. Moreover, synaptic inhi- bition decreases over time, and by 6 months after TBI, it is also significantly decreased contralaterally. Progressive loss of synaptic inhibition is paralleled by a decline in the number of parvalbumin-positive interneurons, but, in contrast to sta- tus epilepticus models, GABAA receptor subunit expression is largely unaltered. At both time points, the magnitude of tonic GABAA receptor-mediated currents after TBI is main- tained, indicating a preservation of the inhibitory constraint of granule cells through tonic inhibition. Our results extend the time window during which strategies to target epilepto- genesis may be effective. © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.