Noradrenergic Circuit Response to Hyperthermia-evoked Seizures in the Mouse Model
Abstract number :
3.026
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2024
Submission ID :
29
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Meiling Zhao, PhD – University of Michigan
Anam Noor, Undergraduate Student – University of Michigan
Chandni Rana, BS – University of Michigan
Christian Burgess, PhD – University of Michigan
Joanna Mattis, MD,PhD – University of Michigan
Rationale: Locus coeruleus (LC) neurons are the main source of noradrenaline released to most brain structures, including the seizure-prone neocortical and limbic regions, regulating numerous physiological progresses including arousal, attention, memory, emotional response, and circuit activity. Previous evidence suggests that LC noradrenergic neurons may be involved in epilepsy and that their activation may be therapeutic for seizures. However, the activity of LC noradrenergic neurons during seizures remains largely unclear.
Methods: We directly investigated the response of noradrenergic neurons to seizures by using Scn1a+/- mice, a well-characterized pre-clinical translational model of Dravet Syndrome (DS) in which seizures can be evoked with hyperthermia. We performed EEG recordings of cortical signal concurrently with fiber photometry recordings of a genetically encoded calcium indicator (GCaMP8s) expressed selectively within LC noradrenergic neurons. We quantified the populational response of noradrenergic neurons before (pre-ictal period), during (ictal period) and after (post-ictal period) seizures. We then measured functional noradrenergic transmission in the hippocampus using the optimized G-Protein-Coupled Receptor-Activation-Based norepinephrine sensor (GRABNE2m). Age-matched, wild-type littermates were heated as a control for effects of hyperthermia.
Results: We found a profound seizure-induced change in the populational activity of LC noradrenergic neurons, with a decrease in the amplitude and frequency of calcium transients, as well as a drop in the baseline calcium activity. This pattern was not observed in wild-type littermate control mice or in heating trials of Scn1a+/- mice that failed to evoke seizures at a similar temperature. We also found a brief elevated release of norepinephrine in the hippocampus around the time of seizure onset, followed by a decrease relative to baseline level.
Conclusions: This study demonstrates that LC noradrenergic neurons are acutely inhibited during hyperthermia-evoked seizures in Scn1a+/- mice. An elevated release level of norepinephrine in the hippocampus is associated with seizure onset and a reduced signal is followed with the progression of seizures. Future studies will involve manipulating LC noradrenergic neurons prior to and during seizures in an attempt to achieve therapeutic benefit in the Scn1a+/- mouse model of DS.
Funding: This project is funded by CURE Epilepsy Taking Flight Award, Taubman Institute Emerging Scholar Award, NIH NINDS K08 NS121464 to J.M and Dravet Syndrome Foundation Postdoc Fellowship to M.Z.
Basic Mechanisms