Seizures in a Dravet Syndrome mouse model inhibit the locus coeruleus but locally evoke supraphysiologic norepinephrine release
- 1University of Michigan
Abstract
Locus coeruleus (LC) neurons are the primary source of norepinephrine / noradrenaline (NE) released to most brain structures, including seizure-prone neocortical and limbic regions. LC-NE networks regulate numerous physiological processes, including arousal, attention, and memory. Previous evidence suggests that LC-NE neurons may be involved in epilepsy and that their activation may have therapeutic effects on seizures, but the endogenous activity of the LC-NE network during seizures remains largely unclear. We combined electrocorticography recordings and in vivo imaging to measure somatic activity of LC-NE neurons as well as downstream NE release during hyperthermia-induced seizures in a well-characterized pre-clinical model of Dravet Syndrome. We found that population LC-NE somatic activity was inhibited during seizures, whereas downstream NE release was dramatically elevated. To reconcile these discordant findings, we established that activation of downstream regions is capable of locally evoking NE release, in part via activation of glutamate receptors, consistent with the Glutamate Amplifies Noradrenergic Effects (GANE) model. Finally, we confirmed that ictal NE release occurred across additional downstream brain regions, epilepsy models, and seizure induction methods. Thus, disruption of NE signaling is likely a widespread ictal signature, with implications for impaired consciousness during and after seizures.
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BibTeX
@misc{zhao2026seizures,
title = {{Seizures in a Dravet Syndrome mouse model inhibit the locus coeruleus but locally evoke supraphysiologic norepinephrine release}},
author = {M. Zhao and Y. Demetriou and A. Noor and J. Barden and L. Zhu and Q. Yu and A. Sajdak and A. Akhaury and C. Rana and P. Yang and Y. Li and C. Burgess and S. McKenzie and P. Kramer and J. H. Mattis},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754424},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754424v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Seizures in a Dravet Syndrome mouse model inhibit the locus coeruleus but locally evoke supraphysiologic norepinephrine release
AU - M. Zhao
AU - Y. Demetriou
AU - A. Noor
AU - J. Barden
AU - L. Zhu
AU - Q. Yu
AU - A. Sajdak
AU - A. Akhaury
AU - C. Rana
AU - P. Yang
AU - Y. Li
AU - C. Burgess
AU - S. McKenzie
AU - P. Kramer
AU - J. H. Mattis
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754424
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754424v1
AB - Locus coeruleus (LC) neurons are the primary source of norepinephrine / noradrenaline (NE) released to most brain structures, including seizure-prone neocortical and limbic regions. LC-NE networks regulate numerous physiological processes, including arousal, attention, and memory. Previous evidence suggests that LC-NE neurons may be involved in epilepsy and that their activation may have therapeutic effects on seizures, but the endogenous activity of the LC-NE network during seizures remains largely unclear. We combined electrocorticography recordings and in vivo imaging to measure somatic activity of LC-NE neurons as well as downstream NE release during hyperthermia-induced seizures in a well-characterized pre-clinical model of Dravet Syndrome. We found that population LC-NE somatic activity was inhibited during seizures, whereas downstream NE release was dramatically elevated. To reconcile these discordant findings, we established that activation of downstream regions is capable of locally evoking NE release, in part via activation of glutamate receptors, consistent with the Glutamate Amplifies Noradrenergic Effects (GANE) model. Finally, we confirmed that ictal NE release occurred across additional downstream brain regions, epilepsy models, and seizure induction methods. Thus, disruption of NE signaling is likely a widespread ictal signature, with implications for impaired consciousness during and after seizures.
ER -