Author:
Dvorak Nolan M.,Domingo Nadia D.,Tapia Cynthia M.,Wadsworth Paul A.,Marosi Mate,Avchalumov Yosef,Fongsaran Chanida,Koff Leandra,Di Re Jessica,Sampson Catherine M.,Baumgartner Timothy J.,Wang Pingyuan,Villarreal Paula P.,Solomon Olivia D.,Stutz Sonja J.,Aditi ,Porter Jacob,Gbedande Komi,Prideaux Brendan,Green Thomas A.,Seeley Erin H.,Samir Parimal,Dineley Kelley T.,Vargas Gracie,Zhou Jia,Cisneros Irma,Stephens Robin,Laezza Fernanda
Abstract
Abstract
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.
Funder
National Institute of Mental Health
National Institute of General Medical Sciences
National Institute of Neurological Disorders and Stroke
National Institute on Aging
Cancer Prevention and Research Institute of Texas
University of Texas Medical Branch
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology,Immunology,General Neuroscience