In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression

• Published in: Communications biology Vol. 7; no. 1; p. 225
• Main Authors: Guet-McCreight, Alexandre, Chameh, Homeira Moradi, Mazza, Frank, Prevot, Thomas D, Valiante, Taufik A, Sibille, Etienne, Hay, Etay
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.02.2024; Nature Portfolio
• Subjects: Allosteric properties; Animal models; Biomarkers; Brain - metabolism; Cognitive ability; Depression - drug therapy; EEG; Humans; Information processing; Interneurons; Interneurons - metabolism; Mental depression; Neuromodulation; Neurons - metabolism; Receptors, GABA-A - metabolism; Somatostatin; γ-Aminobutyric acid A receptors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-05907-1

Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of α5 subunit-containing GABA receptor (α5-PAM) that selectively target this lost inhibition exhibit antidepressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of α5-PAM on the human brain in vivo are unknown, and currently cannot be assessed experimentally. We modeled the effects of α5-PAM on tonic inhibition as measured in human neurons, and tested in silico α5-PAM effects on detailed models of human cortical microcircuits in health and depression. We found that α5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also recovered the power spectral density profile of the microcircuit EEG signals. We performed an α5-PAM dose-response and identified simulated EEG biomarker candidates. Our results serve to de-risk and facilitate α5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy.