Abstract
BackgroundBrain-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 (both in vivo (in models of epilepsy and TBI) and in 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 regulated by agents that inhibit JAK/STAT signaling. Surprisingly, the BDNF-induced JAK/STAT 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 revealed a unique non-canonical mechanism of JAK/STATs in neurons as differential gene expression mediated by STAT3 is not solely dependent upon phosphorylation at residue 705 and may involve a BDNF-induced interaction of STAT3 with Heterochromatin Protein 1 alpha (HP1α).ConclusionsThese findings suggest that the neuronal BDNF-induced JAK/STAT pathway involves more than STAT3 phosphorylation at 705, providing the first evidence for a non-canonical mechanism that may involve HP1α. Our analysis reveals that JAK/STAT signaling regulates many of the genes associated with epilepsy syndromes where BDNF levels are markedly elevated. Uncovering the mechanism of this novel form of BDNF signaling in the brain may provide a new direction for epilepsy therapeutics and open a window into the complex mechanisms of STAT3 transcriptional regulation in neurological disease.
Highlights
Brain-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
The differentially expressed set of transcripts from BDNF-treated primary neurons is highly enriched for genes essential to axonal guidance (p = 1.09E-11); further, there is a striking enrichment that is specific to all major classes of ion channels and neurotransmitter/neuropeptide receptors, with 133 of 599 total genes related to one of these categories regulated by prolonged BDNF exposure (4 h) (p = 2.66E11) (Fig. 2b)
There is a specific decrease (1.73 fold) in the expression of Gaba A receptor alpha 1 subunit (Gabra1) that is a member of the GABAR gene cluster which we have previously demonstrated to be regulated by BDNF using quantitative reverse transcriptase PCR (qRT-PCR) in extracts of BDNF-treated primary neurons and hippocampal tissue extracted from the in vivo PILO model of temporal lobe epilepsy [23]
Summary
Brain-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. We previously found that neurons respond to prolonged BDNF exposure (both in vivo (in models of epilepsy and TBI) and in 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. It has been suggested that neurogenesis [1], mossy fiber sprouting [2], and hippocampal cell death [3] contribute to aberrant neuronal circuit reorganization One manifestation of this reorganization is thought to be altered long-term potentiation (LTP)-induced synaptic plasticity [4], which is associated with altered levels of particular neurotransmitter receptors and ion channels [5, 6]. A conditional deletion of the high-affinity BDNF receptor TrkB in a subset of neurons, is sufficient to completely eliminate all behavioral evidence of the progression of epilepsy in the kindling model [11] and it has been shown that enhanced TrkB signaling can exacerbate epileptogenesis [12]
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