Chemogenetic attenuation of cortical seizures in nonhuman primates

Naohisa Miyakawa; Yuji Nagai; Yukiko Hori; Koki Mimura; Asumi Orihara; Kei Oyama; Takeshi Matsuo; Ken-Ichi Inoue; Takafumi Suzuki; Toshiyuki Hirabayashi; Tetsuya Suhara; Masahiko Takada; Makoto Higuchi; Keisuke Kawasaki; Takafumi Minamimoto

doi:10.1038/s41467-023-36642-6

Chemogenetic attenuation of cortical seizures in nonhuman primates

Nat Commun. 2023 Feb 28;14(1):971. doi: 10.1038/s41467-023-36642-6.

Authors

Affiliations

¹ Department of Functional Brain Imaging, National Institutes for Quantum Science and Technology, Chiba, Japan. nmiyakawa-ns@umin.ac.jp.
² Department of Functional Brain Imaging, National Institutes for Quantum Science and Technology, Chiba, Japan.
³ Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
⁵ Systems Neuroscience Section, Center for the Evolutionary Origins of Human Behavior, Kyoto University, Aichi, Japan.
⁶ Center for Information and Neural Networks, National Institute of Information and Communications Technology, Suita, Japan.
⁷ Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, Chiba, Japan.
⁸ Department of Physiology, Niigata University School of Medicine, Niigata, Japan.
⁹ Department of Functional Brain Imaging, National Institutes for Quantum Science and Technology, Chiba, Japan. minamimoto.takafumi@qst.go.jp.

Abstract

Epilepsy is a disorder in which abnormal neuronal hyperexcitation causes several types of seizures. Because pharmacological and surgical treatments occasionally interfere with normal brain function, a more focused and on-demand approach is desirable. Here we examined the efficacy of a chemogenetic tool-designer receptors exclusively activated by designer drugs (DREADDs)-for treating focal seizure in a nonhuman primate model. Acute infusion of the GABA_A receptor antagonist bicuculline into the forelimb region of unilateral primary motor cortex caused paroxysmal discharges with twitching and stiffening of the contralateral arm, followed by recurrent cortical discharges with hemi- and whole-body clonic seizures in two male macaque monkeys. Expression of an inhibitory DREADD (hM4Di) throughout the seizure focus, and subsequent on-demand administration of a DREADD-selective agonist, rapidly suppressed the wide-spread seizures. These results demonstrate the efficacy of DREADDs for attenuating cortical seizure in a nonhuman primate model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bicuculline / pharmacology
Body Fluids*
Brain
GABA-A Receptor Antagonists
Macaca
Male
Seizures*

Substances

Bicuculline
GABA-A Receptor Antagonists