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

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 larg...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 24; no. 4; p. 3924
Main Authors:	Jada, Reem, Borisov, Veronika, Laury, Eliezer, Halpert, Shmuel, Levy, Nina S, Wagner, Shlomo, Netser, Shai, Walikonis, Randall, Carmi, Ido, Berlin, Shai, Levy, Andrew P
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 15-02-2023 MDPI
Subjects:	Abnormalities AMPA receptor Animal models Animals Arf6-GTP Autism Body temperature Child Children & youth Convulsions & seizures CRISPR Epilepsy Epilepsy - therapy Fever Genetic aspects Guanine Nucleotide Exchange Factors - genetics Heat heat therapy Hot Temperature Humans Hyperthermia, Induced Intellectual disabilities Intellectual Disability - genetics IQSEC2 Mice Morbidity Mortality Mutation Nerve Tissue Proteins - genetics Phenotypes Receptors, AMPA - genetics Seizures Seizures - therapy Thermotherapy α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors Germany Israel Arf6-GTP fever heat therapy AMPA receptor IQSEC2
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms24043924