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TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral
Nolan M Dvorak1, Nadia D Domingo2,3, Cynthia M Tapia1
1Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
Background:
Excess tumor necrosis factor (TNF) is implicated in the pathogenesis of hyperinflammatory experimental cerebral malaria (eCM), including gliosis, increased levels of fibrin(ogen) in the brain, behavioral changes, and mortality. However, the role of TNF in eCM within the brain parenchyma, particularly directly on neurons, remains underdefined. Here, we investigate electrophysiological consequences of eCM on neuronal excitability and cell signaling mechanisms that contribute to observed phenotypes.
Methods:
The split-luciferase complementation assay (LCA) was used to investigate cell signaling mechanisms downstream of tumor necrosis factor receptor 1 (TNFR1) that could contribute to changes in neuronal excitability in eCM. Whole-cell patch-clamp electrophysiology was performed in brain slices from eCM mice to elucidate consequences of infection on CA1 pyramidal neuron excitability and cell signaling mechanisms that contribute to observed phenotypes. Involvement of identified signaling molecules in mediating behavioral changes and sickness behavior observed in eCM were investigated in vivo using genetic silencing.
Results:
Exploring signaling mechanisms that underlie TNF-induced effects on neuronal excitability, we found that the complex assembly of fibroblast growth factor 14 (FGF14) and the voltage-gated Na+ (Nav) channel 1.6 (Nav1.6) is increased upon tumor necrosis factor receptor 1 (TNFR1) stimulation via Janus Kinase 2 (JAK2). On account of the dependency of hyperinflammatory experimental cerebral malaria (eCM) on TNF, we performed patch-clamp studies in slices from eCM mice and showed that Plasmodium chabaudi infection augments Nav1.6 channel conductance of CA1 pyramidal neurons through the TNFR1-JAK2-FGF14-Nav1.6 signaling network, which leads to hyperexcitability. Hyperexcitability of CA1 pyramidal neurons caused by infection was mitigated via an anti-TNF antibody and genetic silencing of FGF14 in CA1. Furthermore, knockdown of FGF14 in CA1 reduced sickness behavior caused by infection.
Conclusions:
FGF14 may represent a therapeutic target for mitigating consequences of TNF-mediated neuroinflammation.
Insights
Excess tumor necrosis factor (TNF) drives experimental cerebral malaria (eCM) neuroinflammation. This study reveals fibroblast growth factor 14 (FGF14) as a key mediator of neuronal hyperexcitability and sickness behavior in eCM, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Excessive tumor necrosis factor (TNF) contributes to hyperinflammatory experimental cerebral malaria (eCM) pathogenesis.
- The precise role of TNF in neuronal dysfunction during eCM remains unclear.
- This study investigates TNF-driven neuronal excitability changes and signaling pathways in eCM.
Purpose of the Study:
- To elucidate the electrophysiological consequences of eCM on neuronal excitability.
- To identify cell signaling mechanisms underlying TNF-induced neuronal dysfunction in eCM.
- To investigate the therapeutic potential of targeting identified pathways in eCM.
Main Methods:
- Split-luciferase complementation assay (LCA) to study signaling downstream of tumor necrosis factor receptor 1 (TNFR1).
- Whole-cell patch-clamp electrophysiology in brain slices from eCM mice to assess CA1 pyramidal neuron excitability.
- In vivo genetic silencing to evaluate the role of signaling molecules in eCM-induced behavioral changes.
Main Results:
- TNF stimulation via TNFR1 increases the complex assembly of fibroblast growth factor 14 (FGF14) and voltage-gated sodium channel 1.6 (Nav1.6) through Janus Kinase 2 (JAK2).
- Plasmodium chabaudi infection augments Nav1.6 channel conductance in CA1 pyramidal neurons via the TNFR1-JAK2-FGF14-Nav1.6 pathway, leading to hyperexcitability.
- Anti-TNF antibody and FGF14 genetic silencing in CA1 mitigated neuronal hyperexcitability and reduced sickness behavior in eCM.
Conclusions:
- The TNFR1-JAK2-FGF14-Nav1.6 signaling network mediates TNF-induced neuronal hyperexcitability in eCM.
- FGF14 is a critical component of the neuroinflammatory cascade in eCM.
- FGF14 inhibition presents a potential therapeutic strategy for managing neuroinflammation and associated symptoms in eCM.
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