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

ABSTRACT: Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of α5 subunit-containing GABA_A 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 powe

SUBMITTER: Guet-McCreight A 

PROVIDER: S-EPMC10891083 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature