title: Progressive loss of phasic, but not tonic, GABAA receptor-mediated inhibition in dentate granule cells in a model of post-traumatic epilepsy in rats.
abstract: 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 dentate gyrus that could contribute to the progressive susceptibility to seizures after TBI. We used severe lateral-fluid percussion brain injury to induce TBI in rats. In this model, spontaneous seizure activity, which involves the hippocampus, appears after a long latent period, resembling the human condition. We demonstrate that synaptic GABA(A) receptor-mediated inhibition is profoundly reduced in ipsilateral dentate granule cells 1 month after TBI. Moreover, synaptic inhibition 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 status epilepticus models, GABA(A) receptor subunit expression is largely unaltered. At both time points, the magnitude of tonic GABA(A) receptor-mediated currents after TBI is maintained, indicating a preservation of the inhibitory constraint of granule cells through tonic inhibition. Our results extend the time window during which strategies to target epileptogenesis may be effective.
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3BG, UK. i.pavlov@ucl.ac.uk
authors.forename: I
authors.initials: I
authors.lastname: Pavlov
authors.forename: N
authors.initials: N
authors.lastname: Huusko
authors.forename: M
authors.initials: M
authors.lastname: Drexel
authors.forename: E
authors.initials: E
authors.lastname: Kirchmair
authors.forename: G
authors.initials: G
authors.lastname: Sperk
authors.forename: A
authors.initials: A
authors.lastname: Pitkänen
authors.forename: M C
authors.initials: MC
authors.lastname: Walker
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000503:physiopathology*; D018891:Dentate Gyrus / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004833:Epilepsy, Temporal Lobe / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D007395:Interneurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*
chemical_list: D011963:Receptors, GABA-A