Temporal lobe epilepsy (TLE) is a neurological disease that is characterized by recurrent unprovoked seizures. The most commonly used animal models of TLE utilize chemoconvulsants to induce prolonged seizures or status epilepticus (SE), which then leads to development of spontaneous recurrent seizures (SRS, epilepsy) after a latent period ranging from days to weeks. Many molecular pathways are activated after SE that may be important contributors to epilepsy;this proposal will focus on neurotrophin signaling. Neurotrophins are growth factors that regulate cell survival, growth, differentiation, and in certain circumstances, cell death. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a myriad of roles in normal brain development including synaptogenesis, neuronal differentiation, and synaptic plasticity. BDNF is first expressed as a precursor, proBDNF, which may then be cleaved to generate mature BDNF (mBDNF). ProBDNF and mBDNF appear to play contrary roles in the nervous system since they primarily activate different receptors, p75NTR and TrkB, respectively. BDNF mRNA levels are increased in the hippocampus after SE in many different models of epilepsy and BDNF has been shown to be an important regulator of epileptogenesis. It is currently unknown whether the effects of BDNF on GABAR a1 subunit expression after status epilepticus are primarily mediated by proBDNF or mBDNF. It has been previously demonstrated that GABAA receptor (GABAR) a1 subunit expression decreases after SE through BDNF activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. My proposal aims to elucidate the possible role of proBDNF on GABAR a1 subunit regulation and epilepsy through activation of the p75NTR and the JAK/STAT pathway. This work, if successful, could impact positively our knowledge in the field of epilepsy since there is little known about the role of proBDNF signaling in epileptogenesis, and potentially lead to new ways of approaching therapeutic interventions.
This work, if successful, could impact positively our knowledge in the field of epilepsy since there is little known about the role of proBDNF signaling in development of epilepsy, and potentially lead to new ways of approaching therapeutic interventions for epilepsy.
