EEG biomarkers of α5-GABA positive allosteric modulators in rodents

Reduced cortical inhibition mediated by gamma-aminobutyric acid (GABA) is reported in depression, anxiety disorders, and aging. Novel positive allosteric modulator that specifically target 5-GABAA receptor subunit (5-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 5-PAM has detectable signatures in clinically-relevant brain electroencephalography (EEG). We analyzed EEG in freely moving rats at baseline and following injections of 5-PAM and DZP. We showed that 5-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 5-PAM has robust and distinct EEG biomarkers in rodents, indicating that EEG could enable non-invasive monitoring of 5-PAM treatment efficacy.