Authors :
Presenting Author: Meiling Zhao, PhD – University of Michigan
Anam Noor, Undergraduate – University of Michigan
Joseph Barden, MS – 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 norepinephrine (NE) released to most brain structures, including the seizure-prone neocortical and limbic regions, regulating numerous physiological progresses including arousal, attention, and memory. Previous evidence suggests that noradrenergic neurons may be involved in epilepsy and that their activation may be therapeutic for seizures. However, the activity of LC-NE network during seizures remains largely unclear.
Methods:
We directly investigated the response of noradrenergic networks to seizures by using Scn1a+/- mice, a well-characterized pre-clinical model of Dravet Syndrome in which seizures can be evoked with hyperthermia. We performed electrocorticography recordings concurrently with fiber photometry and two-photon recordings to measure (1) the activity of LC noradrenergic neurons and (2) downstream NE neurotransmission during seizures.
Results:
We found that LC noradrenergic neurons were inhibited at the populational level during hyperthermia-induced seizures but, surprisingly, downstream NE release was dramatically elevated. In both datasets, we confirmed the absence of these signal changes in wild-type littermate control mice that also underwent hyperthermia, and in heating trials of Scn1a+/- mice that failed to evoke seizures. To reconcile these discordant findings, we tested and validated the Glutamate Amplifies Noradrenergic Effects (GANE) theory, in which excitatory activity in downstream regions locally evokes NE release, independent of somatic LC activation.
Conclusions:
In sum, our result has identified an intriguingly discordant finding: seizures are associated with a decrease in LC-NE neuronal activity, but an acute increase in downstream NE levels, likely triggered by local neuronal activation of NE release. Future work will examine the functional implications of these seizure-associated disruptions to NE circuitry.
Funding:
CURE Epilepsy Taking Flight Award (JM), NIH NINDS K08 NS121464 (JM), Taubman Institute Emerging Scholar Award - Kenneth Eisenberg Emerging Scholar (JM), UMMS Research Scouts Award (JM), Dravet Syndrome Foundation Postdoctoral Fellowship (MZ).