Effects of TrkB Activation on Abnormalities in Neocortical FS interneuron

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Project Summary Abnormalities in parvalbumin (PV) and somatostatin (SOM) interneurons are reported in a number of neurological disorders, including epilepsy. Therapy that improves function of defective interneurons is not available. Structural development and maintenance of interneurons is dependent on trophic support provided by brain derived neurotrophic factor activation of TrkB receptors (TrkB-Rs). In the undercut (UC) model of epileptogenic neocortical injury, chronic activation of TrkB-Rs with a selective small molecule partial agonist (LM22A-4, “LM” below) has long-term effects to reverse structural and functional abnormalities in inhibitory terminals of PV interneurons, enhance GABA release and increase the threshold for evoking epileptiform activity and seizures. The parent grant main goal is to determine whether these effects will be applicable to treatment or prevention of epilepsy in other models with different causes for seizures. The objective is to determine whether chronic treatment with a TrkB-Rs partial agonist, by increasing GABA release from nerve terminals of interneurons, or inducing new inhibitory synapse formation, will enhance inhibition in cortical networks and suppress epileptiform discharges. The specific aims of the parent grant include to: i) test the hypothesis that activation of TrkB-Rs with LM will reverse or prevent structural abnormalities in FS interneurons of UC cortex; ii) Examine effects of TrkB-Rs activation on functional properties of GABAergic inhibition in layer V; iii) Test the effects of LM on cortical network activity in UC animals. Proposed experiments include a) immunocytochemistry and confocal imaging to assess alterations in presynaptic terminals of interneurons; b) electrophysiological analysis of basic properties of inhibitory synaptic transmission from PV interneurons to pyramidal neurons of in vitro slices to detect effects of TrkB activation on unitary IPSCs, release probability and transmission failures. For this supplement grant we will study the effects of focal status epilepticus (FSE) on numbers, morphology and physiology of GABAergic interneurons in the cortical network and test possible mitigating effects of activation of TrkB-Rs with a small molecule partial agonist, PTXBD4-3 (BD). These results will complement and extend Aims 1, and 2 of the parent grant. Results of these experiments will provide information about mechanisms leading from interneuronal abnormalities to development of epilepsy and a potential approach to prophylaxis of epileptogenesis by enhancing trophic support of interneurons. Considering the frequency and untoward consequences of FSE, results may have potential translational importance.