Abstracts

Rationale: The principal molecular targets of conventional antiseizure drugs consist of ligand-gated and voltage-gated ion channels and proteins subserving synaptic function. Inhibition of the receptor tyrosine kinase TrkB limits epileptogenesis, but its effect on individual seizures is unknown. We sought to determine whether inhibition of TrkB kinase exerts an antiseizure effect. Methods: We utilized the kindling model in combination with an inducible conditional knock-out of the TrkB gene (Act-CreER TrkB^flox/flox mice treated with tamoxifen), and also with a chemical-genetic approach in which mice carry a TrkB kinase with a phenyl-alanine to alanine substitution of residue 616 (TrkB^F616A), which allows inhibition of the kinase by a blood-brain barrier permeable small molecule, 10-naphthylmethyl-4- amino-1-tert-butyl-3-(p-methylphenyl)pyrazolo[3,4-d]pyrimidine (1NMPP1). Results: Following induction of kindling, reduction of TrkB protein levels in Act-CreER TrkB^flox/flox mice treated with tamoxifen was associated with reduced severity of behavioral seizures evoked by stimulation. Treatment with 1NMPP1 for 2 weeks following induction of kindling reversibly elevated both focal electrographic and generalized seizure thresholds in TrkB^F616A, but not wild-type (WT), mice. In contrast to kindled ani- mals, treatment of naive TrkB^F616A mice for 2 weeks had no detectable effect on electrographic seizure threshold (EST). Conclusions: This study provides proof of concept of a novel molecular target for anti-seizure drugs, namely the receptor tyrosine kinase TrkB.