Activation of Hippocampal Gabaergic Neurons with Luminopsins Reduces Pentylenetetrazole-induced Spike-and-wave Discharges in Mice
Abstract number :
3.15
Submission category :
2. Translational Research / 2E. Other
Year :
2022
Submission ID :
2205036
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Alejandra Fernandez, PhD – Emory University School of Medicine; Sang-Eon Park, PhD – Korea Advanced Institute of Science and Technology; Ken Berglund, PhD – Emory University School of Medicine; Claire-Anne Gutekunst, PhD – Emory University School of Medicine; Robert Gross, MD, PhD – Emory University School of Medicine
Rationale: Approximately one third of patients with epilepsy do not respond to currently available antiseizure drugs, and many are not candidates for surgical resection. Thus, there is a great need for novel alternative treatment modalities. We have developed a hardware-independent chemogenetic tool, called luminopsins, consisting of a light-sensitive channel fused with a luciferase enzyme that bioluminesces in the presence of its substrate coelenterazine (CTZ). We previously showed that inhibition of glutamatergic neurons in the dentate gyrus and anterior thalamic nucleus, with an inhibitory luminopsin, reduces seizure severity and duration in a pentylenetetrazole (PTZ) seizure model.
Methods: In this study, we specifically activated GABAergic neurons in dorsal and ventral hippocampus with the goal of achieving greater seizure control. We hypothesized that activation of GABAergic neurons suppresses electrographic spike-and-wave discharges (SWDs) and behavioral events in the PTZ model. To test this, VGAT-Cre mice received bilateral injections of the excitatory luminopsin gene into dorsal and ventral hippocampi. Mice were implanted with EEG screws and hippocampal depth electrodes and subjected to a PTZ test two weeks after virus injection. Mice were pretreated with either vehicle or CTZ 20 minutes before PTZ injection and monitored for 45 minutes. One week later, this procedure was repeated in the same mice with the opposite treatment.
Results: Post-mortem histology showed adequate expression of the excitatory luminopsin throughout the entire hippocampus. CTZ-treated mice showed a reduction in the number of SWDs as well as in the fraction of time spent in SWDs. SWD duration remained unchanged._x000D_
Conclusions: Our results show that activation of hippocampal GABAergic neurons has the ability to reduce epileptiform activity in a generalized seizure model. Our results underscore the importance of inhibitory circuits in a seizure-prone state.
Funding: Mirowksi Family Foundation
Translational Research