Abstract
Reduced cortical inhibition mediated by gamma-aminobutyric acid (GABA) is reported in depression, anxiety disorders, and aging. Novel positive allosteric modulator that specifically target α5-GABAA receptor subunit (α5-PAM), ligand GL-II-73, shows anxiolytic, antidepressant, and pro-cognitive effects without the common side effects associated with non-specific modulation by benzodiazepines such as diazepam (DZP), thus suggesting novel therapeutic potential. However, it is unknown if α5-PAM has detectable signatures in clinically-relevant brain electroencephalography (EEG). We analyzed EEG in freely moving rats at baseline and following injections of α5-PAM and DZP. We showed that α5-PAM specifically decreased theta peak power whereas DZP shifted peak power from high to low theta, while increasing beta and gamma power. EEG decomposition showed that these effects were periodic and corresponded to changes in theta oscillation event duration. Our study thus shows that α5-PAM has robust and distinct EEG biomarkers in rodents, indicating that EEG could enable non-invasive monitoring of α5-PAM treatment efficacy.
Competing Interest Statement
ES and TP are listed inventors on patents covering syntheses and use of α5-PAM compounds (Title: Treatment of Cognitive and mood systems in Neurodegenerative and Neuropsychiatric disorders with Alpha 5 - containing GABAA selective agonist, US, Canada, EU, JP, Australia, 62/310409; Title: Compositions And Methods Relating To Use Of Agonists Of Alpha5- Containing Gabaa Receptors, US, Canada, EU, JP, Australia, 62/805009; Title: Imidazobenzodiazepines for treatment of cognitive and mood symptoms, US, Canada, EU, JP, Australia, PCT/US2022/042832). EH, ES, and TP are listed inventors and AGM, FM and TAV are listed as collaborators on a patent covering in-silico EEG biomarkers for monitoring α5-PAM treatment efficacy (Title: EEG biomarkers for Alpha5-PAM therapy, United States of America, 63/382,577). ES is the Founder and CSO, and TP is the Director of Operations of Damona Pharmaceuticals, a biopharma dedicated to bringing α5-PAMcompounds to the clinic.
Footnotes
Revised title (order of the word GABA and α5)