Transcriptomic analysis of the BDNF-induced JAK/STAT pathway in neurons: a window into epilepsy-associated gene expression

Abstract

AbstractBackgroundBrain-derived neurotrophic factor (BDNF) is a major signaling molecule that the brain uses to control a vast network of intracellular cascades fundamental to properties of learning and memory, and cognition. While much is known about BDNF signaling in the healthy nervous system where it controls the mitogen activated protein kinase (MAPK) and cyclic-AMP pathways, less is known about its role in multiple brain disorders where it contributes to the dysregulated neuroplasticity seen in epilepsy and traumatic brain injury (TBI). We previously found that neurons respond to prolonged BDNF exposure (bothin vivo(in models of epilepsy and TBI) andin vitro(in BDNF treated primary neuronal cultures)) by activating the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway. This pathway is best known for its association with inflammatory cytokines in non-neuronal cells.ResultsHere, using deep RNA-sequencing of neurons exposed to BDNF in the presence and absence of well characterized JAK/STAT inhibitors, and without non-neuronal cells, we determine the BDNF transcriptome that is specifically reliant on JAK/STAT signaling. Surprisingly, the transcriptome contains ion channels and neurotransmitter receptors coming from all the major classes expressed in the brain, along with key modulators of synaptic plasticity, neurogenesis, and axonal remodeling. Analysis of this dataset has also provided a window on the unique mechanism of JAK/STATs in neurons as differential gene expression mediated by STAT3 does not appear to be dependent upon phosphorylation at residue 705.ConclusionsOur findings strengthen and expand the role that BDNF plays in the regulation of brain excitability at the transcriptional level. They also suggest that a majority of such signaling in neurons is tied to the activation of the JAK/STAT pathway which may be non-canonical, not based on phosphorylation of STAT3 proteins at Tyrosine 705.