Daily Brief Heat Therapy Reduces Seizures in A350V IQSEC2 Mice and Is Associated with Correction of AMPA Receptor-Mediated Synaptic Dysfunction

Reem Jada, Veronika Borisov, Eliezer Laury, Shmuel Halpert, Nina S. Levy, Shlomo Wagner, Shai Netser, Randall Walikonis, Ido Carmi, Shai Berlin, Andrew P. Levy

Research output: Contribution to journalArticlepeer-review


Purposeful induction of fever for healing, including the treatment of epilepsy, was used over 2000 years ago by Hippocrates. More recently, fever has been demonstrated to rescue behavioral abnormalities in children with autism. However, the mechanism of fever benefit has remained elusive due in large part to the lack of appropriate human disease models recapitulating the fever effect. Pathological mutations in the IQSEC2 gene are frequently seen in children presenting with intellectual disability, autism and epilepsy. We recently described a murine A350V IQSEC2 disease model, which recapitulates important aspects of the human A350V IQSEC2 disease phenotype and the favorable response to a prolonged and sustained rise in body core temperature in a child with the mutation. Our goal has been to use this system to understand the mechanism of fever benefit and then develop drugs that can mimic this effect and reduce IQSEC2-associated morbidity. In this study, we first demonstrate a reduction in seizures in the mouse model following brief periods of heat therapy, similar to what was observed in a child with the mutation. We then show that brief heat therapy is associated with the correction of synaptic dysfunction in neuronal cultures of A350V mice, likely mediated by Arf6-GTP.

Original languageAmerican English
Article number3924
Issue number4
StatePublished - 15 Feb 2023


  • AMPA receptor
  • Animals
  • Arf6-GTP
  • Child
  • Epilepsy/genetics
  • Epilepsy/therapy
  • Guanine Nucleotide Exchange Factors/genetics
  • Hot Temperature
  • Humans
  • Hyperthermia, Induced
  • IQSEC2
  • Intellectual Disability/genetics
  • Mice
  • Mutation
  • Nerve Tissue Proteins/genetics
  • Nerve Tissue Proteins/metabolism
  • Receptors, AMPA/genetics
  • Seizures/genetics
  • Seizures/therapy
  • fever
  • heat therapy

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry


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