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

Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Brain derived neurotrophic factor (BDNF) plays an important role in development, differentiation, and survival of neurons. However, alterations in BDNF expression also occur in a number of neurological disorders including epilepsy, and its comorbidities (cognitive impairment and depression). Many laboratories have identified BDNF as a key component in epileptogenesis, linking ineffective inhibitory neurotransmission to seizure susceptibility in temporal lobe epilepsy (TLE). γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, and its type A receptor (GABAARs), are believed to play a significant role in epilepsy development, as altered GABAAR subunit composition may contribute to epilepsy susceptibility in TLE. The Russek laboratory, in collaboration with Dr. Brooks-Kayal, discovered that BDNF is a key regulator of GABAAR composition, as it increases α4-containing GABAARs and decreases α1-containing GABAARs, the major synaptic GABAAR in neurons. This thesis provides further evidence that BDNF inhibits αl synthesis via activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling that promotes expression of inducible cAMP early repressor (ICER), whose target is the αl-subunit gene (Gabral). The overarching hypothesis is that prolonged seizures increase levels of BDNF, which alter brain inhibition via activation of the JAK/STAT pathway. Over time these changes in inhibition contribute to epileptogenesis, or the development of epilepsy. How BDNF-signaling activates the JAK/STAT pathway to contribute to decreased Cabral expression was not known. Studies of this thesis suggest that a novel BDNF receptor/signaling pathway regulates such changes. BDNF binds two receptors, tropomysin related kinase B (TrkB) and p75 neurotrophin receptor (NTR). Alterations in neurotrophin receptor expression are observed in animal models of epilepsy. Thesis results show that exposure to recombinant BDNF autologously regulates neurotrophin receptor expression in primary cortical neurons in a manner similar to what is observed in models of epilepsy, reducing levels of TrkB and increasing p7SNTR. These findings suggest a distinct relationship between BDNF and the expression of its receptors. Taken together, the working hypothesis is that BDNF regulates Cabral expression through a selective activation of neurotrophin receptors that is coupled directly to the JAK/STAT pathway. This pathway controls ICER synthesis to directly repress Cabral transcription