Hyperexcitable but seizure-free: hippocampal network dysfunction in a Wolfram syndrome model
- 1Washington University School of Medicine
Abstract
Wolfram syndrome (WS) is a rare, life-limiting progressive neurodegenerative disorder caused by pathogenic variants in the WFS1 gene. It is a prototype endoplasmic reticulum (ER) stress disorder, and the mechanisms underlying neurological phenotypes in WS remain incompletely understood. Although WFS1 protein is abundant in the hippocampus, the role of this region in WS remains relatively understudied. Here we characterize hippocampal function across scales in mice carrying a patient orthologous Wfs1 variant (p.W542*) on both alleles. Male mutants lose excitatory synapses, and dissociated hippocampal neurons are markedly hyperexcitable yet generate no increase in network bursting and no shift in network criticality, indicating that their additional firing is not recruited into coordinated population activity. This finding translates in vivo wherein intracranial electroencephalogram (EEG) recordings show no epileptiform activity or seizures in either sex, with no hippocampal astrogliosis, alongside a male-specific reduction in hippocampal low-gamma power. Additionally, EEG demonstrates a sex-specific disruption of sleep, which parallels a sex-divergent synaptic phenotype. Mutant male mice show impaired hippocampus-dependent fear memory and reduced voluntary motor activity. Taken together, we propose that cellular hyperexcitability in the WS hippocampus does not translate into increased network bursting, potentially due to disproportionate loss of excitatory synapses. This dissociation may provide a functional substrate for the neurological features of WS.
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BibTeX
@misc{ahmadi2026hyperexcitable,
title = {{Hyperexcitable but seizure-free: hippocampal network dysfunction in a Wolfram syndrome model}},
author = {S. Ahmadi and J. G. Pinera and S. Dokholyan and A. D. Sauerbeck and H. N. Phan and B. Carman and A. Debnath and S. Brunwasser and G. Skinner and N. Rensing and M. Wong and C. Cearlock and S. E. Maloney and T. T. Kummer and S. Singamaneni and J. Cirrito and T. J. Foutz and F. Urano},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.27.754840},
url = {https://www.biorxiv.org/content/10.64898/2026.09.27.754840v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Hyperexcitable but seizure-free: hippocampal network dysfunction in a Wolfram syndrome model
AU - S. Ahmadi
AU - J. G. Pinera
AU - S. Dokholyan
AU - A. D. Sauerbeck
AU - H. N. Phan
AU - B. Carman
AU - A. Debnath
AU - S. Brunwasser
AU - G. Skinner
AU - N. Rensing
AU - M. Wong
AU - C. Cearlock
AU - S. E. Maloney
AU - T. T. Kummer
AU - S. Singamaneni
AU - J. Cirrito
AU - T. J. Foutz
AU - F. Urano
PY - 2026
DA - 2026/09/27
PB - bioRxiv
DO - 10.64898/2026.09.27.754840
UR - https://www.biorxiv.org/content/10.64898/2026.09.27.754840v1
AB - Wolfram syndrome (WS) is a rare, life-limiting progressive neurodegenerative disorder caused by pathogenic variants in the WFS1 gene. It is a prototype endoplasmic reticulum (ER) stress disorder, and the mechanisms underlying neurological phenotypes in WS remain incompletely understood. Although WFS1 protein is abundant in the hippocampus, the role of this region in WS remains relatively understudied. Here we characterize hippocampal function across scales in mice carrying a patient orthologous Wfs1 variant (p.W542*) on both alleles. Male mutants lose excitatory synapses, and dissociated hippocampal neurons are markedly hyperexcitable yet generate no increase in network bursting and no shift in network criticality, indicating that their additional firing is not recruited into coordinated population activity. This finding translates in vivo wherein intracranial electroencephalogram (EEG) recordings show no epileptiform activity or seizures in either sex, with no hippocampal astrogliosis, alongside a male-specific reduction in hippocampal low-gamma power. Additionally, EEG demonstrates a sex-specific disruption of sleep, which parallels a sex-divergent synaptic phenotype. Mutant male mice show impaired hippocampus-dependent fear memory and reduced voluntary motor activity. Taken together, we propose that cellular hyperexcitability in the WS hippocampus does not translate into increased network bursting, potentially due to disproportionate loss of excitatory synapses. This dissociation may provide a functional substrate for the neurological features of WS.
ER -