TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria

Nolan M Dvorak; Nadia D Domingo; Cynthia M Tapia; Paul A Wadsworth; Mate Marosi; Yosef Avchalumov; Chanida Fongsaran; Leandra Koff; Jessica Di Re; Catherine M Sampson; Timothy J Baumgartner; Pingyuan Wang; Paula P Villarreal; Olivia D Solomon; Sonja J Stutz; Aditi; Jacob Porter; Komi Gbedande; Brendan Prideaux; Thomas A Green; Erin H Seeley; Parimal Samir; Kelley T Dineley; Gracie Vargas; Jia Zhou; Irma Cisneros; Robin Stephens; Fernanda Laezza

doi:10.1186/s12974-023-02992-7

TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria

J Neuroinflammation. 2023 Dec 19;20(1):306. doi: 10.1186/s12974-023-02992-7.

Authors

Nolan M Dvorak¹, Nadia D Domingo^{2

3}, Cynthia M Tapia¹, Paul A Wadsworth¹, Mate Marosi¹, Yosef Avchalumov¹, Chanida Fongsaran³, Leandra Koff¹, Jessica Di Re¹, Catherine M Sampson¹, Timothy J Baumgartner¹, Pingyuan Wang¹, Paula P Villarreal^{4

5}, Olivia D Solomon⁴, Sonja J Stutz⁶, Aditi⁷, Jacob Porter⁸, Komi Gbedande^{2

9}, Brendan Prideaux⁴, Thomas A Green¹, Erin H Seeley⁸, Parimal Samir⁷, Kelley T Dineley⁶, Gracie Vargas⁴, Jia Zhou¹, Irma Cisneros³, Robin Stephens^{10

11

12}, Fernanda Laezza¹³

Affiliations

¹ Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
² Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX, 77555, USA.
³ Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
⁴ Department of Neurobiology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
⁵ Clinical Sciences Program, The Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX, 77555, USA.
⁶ Center for Addiction Sciences and Therapeutics, University of Texas Medical Branch, Galveston, TX, 77555, USA.
⁷ Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
⁸ Department of Chemistry, University of Texas, Austin, TX, 78712, USA.
⁹ Center for Immunity and Inflammation and Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ, 07301, USA.
¹⁰ Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX, 77555, USA. Robin.Stephens@Rutgers.edu.
¹¹ Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA. Robin.Stephens@Rutgers.edu.
¹² Center for Immunity and Inflammation and Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ, 07301, USA. Robin.Stephens@Rutgers.edu.
¹³ Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, USA. felaezza@utmb.edu.

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⁺ (Na_v) channel 1.6 (Na_v1.6) 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 Na_v1.6 channel conductance of CA1 pyramidal neurons through the TNFR1-JAK2-FGF14-Na_v1.6 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.

Keywords: Hippocampus; Ion channels; Neuroinflammation; Neuronal excitability; Phosphorylation; Synaptic plasticity; Therapeutic target.

MeSH terms

Animals
Illness Behavior*
Malaria, Cerebral*
Mice
NAV1.6 Voltage-Gated Sodium Channel / metabolism
Neurons / metabolism
Receptors, Tumor Necrosis Factor, Type I / genetics
Receptors, Tumor Necrosis Factor, Type I / metabolism
Signal Transduction
Tumor Necrosis Factor Inhibitors

Substances

fibroblast growth factor 14
Receptors, Tumor Necrosis Factor, Type I
Tumor Necrosis Factor Inhibitors
NAV1.6 Voltage-Gated Sodium Channel

Abstract

MeSH terms

Substances

Grants and funding