Disease Modification of Epilepsy by Disruption of TrkB Signaling

Abstract

Epilepsy is the most common acquired neurological disorder and is characterized by spontaneous, recurrent seizures. Of the various forms of epilepsy, Temporal Lobe Epilepsy (TLE) has received intense clinical and research interest. Current therapeutic options for TLE are anti-convulsive and purely symptomatic. Improved treatments are needed that either (1) prevent epileptogenesis or (2) ameliorate existing disease. Studies suggest that TLE may be induced by a preceding episode of prolonged seizure activity (status epilepticus, or SE). Our lab previously utilized a chemical-genetic strategy to establish proof of concept that transient inhibition of the receptor tyrosine kinase TrkB following SE prevented TLE. Subsequent studies identified the downstream effector of TrkB activation by demonstrating that transient administration of a peptide (“pY816”) uncoupling TrkB from the enzyme PLCγ1 also prevented SE-induced TLE. TLE is analogous to associative memory formation in that both involve activity-determined plasticity. Associative memories can be rendered labile following re-exposure to the inciting stimulus; during this labile period inhibition of molecular mechanisms necessary for initial learning inhibits reconsolidation and results in memory “erasure”. Given the proposed parallels between epileptogenesis and memory formation as well as the central role of TrkB-PLCγ1 signaling in the development of epilepsy, I sought to test whether the occurrence of a seizure introduces a period of lability and whether inhibition of TrkB-PLCγ1 signaling prevents subsequent reconsolidation. I demonstrate in the kindling model of TLE that the combination of an evoked seizure and chemical-genetic inhibition of TrkB kinase, but not inhibition of TrkB kinase alone, reduces the severity of subsequent evoked seizures. Combination of an evoked seizure and pY816 (but not pY816 alone) produces the same effect. These results suggest that seizures induce a period of lability in a model of TLE and perturbation of TrkB-PLCγ1 signaling inhibits reconsolidation of pathologic plasticity. In specimens from patients who underwent surgical resection for medically refractory TLE there is a striking increase in expression of the ligand for TrkB, BDNF. In a second study, I demonstrate that this increase, as well as an increase in TrkB-PLCγ1 signaling, is also seen in a TLE model exhibiting spontaneous seizures. Given the result that TrkB-PLCγ1 inhibition prevents reconsolidation, I asked what effect treatment with pY816 has in an animal model after spontaneous seizures emerged. I demonstrate that pY816 induced a remission in seizures that persists after treatment termination. These studies elucidate a signaling pathway (TrkB-PLCγ1) underlying epilepsy progression and persistence, connect TLE to other disorder of pathologic plasticity like PTSD and neuropathic pain, and open the door to a novel therapeutic approach for treating patients with existing epilepsy.