BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons
Hokenson, Kristen Elizabeth
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Epilepsy is a neurological disorder that causes recurrent and unprovoked seizures due to imbalances in synaptic transmission in distinct regions of the brain. In both human patients and animal models of epilepsy, there is a marked increase in brain-derived neurotrophic factor (BDNF), a critical signaling molecule in the brain that contributes to two divergent pathways important to disease pathology: 1) the regulation of type A receptors for the major inhibitory neurotransmitter GABA (GABAARs), and 2) aberrant neurogenesis with ectopic expression of new neurons from progenitor cells that disrupt neural network activity in the hippocampus. The first part of my thesis addresses how neurons regulate levels of α1-containing GABAARs through BDNF signaling at its receptors, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR). I hypothesized and showed that BDNF, working at TrkB, rapidly activates the Janus kinase and signal transducers and activators of transcription (JAK/STAT) pathway in neurons and identified a novel intracellular receptor signaling complex composed of p75NTR and JAK2 that is present in neuronal processes, cell body, and nucleus. Based on this finding, we suggest that an intracellular p75NTR/JAK2 signalsome recruits STAT3, a transcriptional activator of the gene coding for the cAMP inducible early repressor (ICER) that blocks synthesis of α1 subunits reducing synaptic GABAARs in response to status epilepticus. This model is consistent with our collaborative studies that show a JAK2 inhibitor, WP1066, inhibits development of spontaneous seizures in an epilepsy model and my observation that WP1066 degrades JAK2 protein in primary neurons. The second part of my thesis addresses BDNF regulation of the Late SV40 Factor (LSF), a ubiquitous transcription factor that regulates cell cycle progression and survival. I show that BDNF through the mitogen-activated protein kinase pathway selectively phosphorylates LSF at serine 291 (p291LSF) and that p291LSF is present throughout neurogenesis, increases with status epilepticus in the hippocampus, and is highest in structures associated with neurogenesis (such as olfactory bulb and hippocampus when compared to cortex). Taken together, these results suggest LSF may play an important role in neuronal development and potentially in epilepsy, providing an additional target for future therapeutic intervention.