Abstracts

Rationale: Decreased GABAergic inhibition due to abnormalities of interneurons plays a critical role in epileptogenesis following traumatic brain injury. To prevent post-traumatic epileptogenesis (PTE), it is important to develop an effective way to improve the function of interneurons in the injured brain. Methods: To test the hypothesis that enhanced trophic support would improve interneuronal function and decrease epileptogenesis, we used the partial neocortical isolation (undercut or UC) model in rats that were treated intranasally and intraperitoneally for 2 weeks beginning the day of injury with LM22A-4, a newly-designed partial agonist at the BDNF TrkB receptor. Effects of TrkB activation were assessed by measuring pAKT/AKT with Western blots, by examining functional and structural properties of GABAergic interneurons, and recording epileptiform discharges in the UC model of post-traumatic epilepsy. Results: Our results in UC animals show that 1) LM22A-4 treatment significantly increases the frequency of sIPSCs and mIPSCs; 2) LM22A-4 treatment results in an increase in pyramidal cell perisomatic volume of immunoreactivity for both VGAT and GAD65; 3) LM22A-4 treatment significantly decreases the incidence of spontaneous epileptiform bursts, as well as those evoked by electrical stimulation or by perfusion of slices from UC cortex with ACSF containing low concentration of bicuculline. Conclusions: These results indicate that chronic TrkB activation by a partial agonist after cortical injury can suppress PTE by improving functional GABAergic inhibition and anatomical abnormalities in GABAergic interneurons. Although the full agonist effects of BDNF and TrkB in epilepsy models have been controversial, the present results indicate that TrkB activation by a partial agonist may potentially serve as an effective therapeutic option for prophylactic treatment of PTE, and treatment of other neurological disorders, whose pathogenesis involves impaired inhibitory interneuronal function.