Electroencephalography Biomarkers of α5-GABA Positive Allosteric Modulators in Rodents

Frank Mazza; Alexandre Guet-McCreight; Thomas D Prevot; Taufik Valiante; Etienne Sibille; Etay Hay

doi:10.1016/j.bpsgos.2024.100435

Electroencephalography Biomarkers of α5-GABA Positive Allosteric Modulators in Rodents

Biol Psychiatry Glob Open Sci. 2024 Dec 19;5(2):100435. doi: 10.1016/j.bpsgos.2024.100435. eCollection 2025 Mar.

Authors

Frank Mazza^{1

2}, Alexandre Guet-McCreight¹, Thomas D Prevot^{3

4}, Taufik Valiante^{5

6

7

8

9

10

11}, Etienne Sibille^{3

4

12}, Etay Hay^{1

2

3}

Affiliations

¹ Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
² Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
³ Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
⁴ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
⁵ Krembil Brain Institute, University Healthy Network, Toronto, Ontario, Canada.
⁶ Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada.
⁷ Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
⁹ Center for Advancing Neurotechnological Innovation to Application, Toronto, Ontario, Canada.
¹⁰ Max Planck-University of Toronto Center for Neural Science and Technology, Toronto, Ontario, Canada.
¹¹ Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
¹² Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.

Abstract

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.

Keywords: Biomarkers; Depression; Electroencephalography; Inhibition; Pharmacology; Rodents.

Plain language summary

Reduced cortical inhibition is reported in depression, anxiety disorders, and aging. Novel α5-PAM pharmacology specifically targeting α5-GABA_A receptors shows anxiolytic, antidepressant, and procognitive effects without the common side effects of nonspecific GABA_A-targeting drugs such as diazepam. However, it is unknown whether α5-PAM has detectable signatures in clinically relevant EEG signals. We showed that α5-PAM has specific EEG biomarkers in freely moving rats, decreasing peak power in theta frequencies, in contrast to diazepam, which shifted peak power from high to low theta. Thus, our study indicates that EEG could enable noninvasive monitoring of α5-PAM treatment efficacy.