Electroencephalography Biomarkers of α5-GABA Positive Allosteric Modulators in Rodents.

BACKGROUND: Reduced cortical inhibition mediated by GABA (gamma-aminobutyric acid) is reported in depression, anxiety disorders, and aging. A novel positive allosteric modulator that specifically targets the α5-GABA(A) receptor subunit (α5-PAM), ligand GL-II-73 shows anxiolytic, antidepressant, and procognitive effects without the common side effects associated with nonspecific modulation by benzodiazepines such as diazepam, thus suggesting novel therapeutic potential. However, it is unknown whether α5-PAM has detectable signatures in clinically relevant brain electroencephalography (EEG). METHODS: We analyzed EEG in 10 freely moving rats at baseline and following injections of α5-PAM (GL-II-73) and diazepam. RESULTS: We showed that α5-PAM specifically decreased theta peak power, whereas diazepam 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. CONCLUSIONS: Thus, our study shows that α5-PAM has robust and distinct EEG biomarkers in rodents, indicating that EEG could enable noninvasive monitoring of α5-PAM treatment efficacy.