BDNF and JAK/STAT: partners in seizure-induced GABA-A receptor downregulation

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DESCRIPTION (provided by applicant): Epilepsy is a neurological disorder characterized by recurrent seizures, affecting more than 50 million people worldwide. Temporal lobe epilepsy (TLE) is a common form of epilepsy, where seizures arise from the temporal lobe. TLE can be debilitating, as many patients experience impaired memory function and depression, or suffer seizure-related injuries due to loss of consciousness. Furthermore, up to 50,000 people die each year from seizures and related causes. With the potential for such serious health risks it is important to understand the molecular mechanisms behind TLE to better treat the disorder. Epileptic neurons exhibit distinct activity during seizures, controlled by neurotransmitters including 3-aminobutyric acid (GABA). Altered type A GABA receptor composition may contribute to seizure susceptibility. In particular, an upregulation of 14 and a downregulation of 11 subunits are observed after prolonged seizures in humans and in TLE animal models. Our laboratory has identified brain derived neurotrophic factor (BDNF) as a key regulator that mediates 11 downregulation through its activation of the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) pathway, that controls expression of inducible cAMP early repressor (ICER). Our general hypothesis is that BDNF signals through the JAK/STAT pathway to downregulate 11 expression after status epilepticus (SE), resulting in impaired inhibition that plays a critical role in the process of epileptogenesis. Using a variety of techniques including gene silencing in culture and in vivo, chromatin immunoprecipitation (ChIP), and co-immunoprecipitation of protein/protein interactions, specific components of the JAK/STAT signaling pathway activated by either the pro- or mature forms of BDNF will be identified. We will also determine whether there is a direct association of neurotrophin receptors TrkB and p75NTR with the JAK/STAT complex, as well as the potential role of JAK/STAT activation to epileptogenesis in the pilocarpine TLE model. The proposed studies lay the foundation for directly identifying distinct members of the BDNF- induced JAK/STAT pathway activated by SE, with the promise of providing novel therapeutic targets for future treatment of intractable epilepsy as well as other disorders that display reduced 11 subunit expression. PUBLIC HEALTH RELEVANCE: Epilepsy is a neurological disorder affecting more than 50 million people worldwide (Epilepsy Foundation, 2008). Alterations in neurotransmitter receptor subunits may contribute to seizure susceptibility in one form of epilepsy, temporal lobe epilepsy. The proposed studies will examine the signaling pathway contributing to these changes with the hope of identifying novel targets for more effective treatment of epilepsy.