In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression.
Commun Biol
; 7(1): 225, 2024 Feb 23.
Article
in En
| MEDLINE
| ID: mdl-38396202
ABSTRACT
Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of α5 subunit-containing GABAA 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Receptors, GABA-A
/
Depression
Limits:
Humans
Language:
En
Journal:
Commun Biol
Year:
2024
Type:
Article
Affiliation country:
Canada