Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits

Cortical processing depends on finely-tuned excitatory and inhibitory connections in neuronal microcircuits. In major depressive disorder (depression), a disrupted balance due to weaker inhibition by somatostatin-expressing interneurons is implicated in cognitive deficits and rumination symptoms. Here, we tested the impact of reduced somatostatin interneuron inhibition on cortical processing in human microcircuits in depression using a data-driven computational approach. We integrated human cellular, circuit and gene-expression data to generate detailed models of human cortical microcircuits in health and depression. We simulated microcircuit baseline and response activity and found reduced signal-to-noise ratio of cortical processing, and increased false/failed detection of stimuli, due to a higher baseline activity (noise) in depression. Our results demonstrate mechanistically how reduced inhibition in human neuronal microcircuits impairs cortical processing in depression, thus establishing a target mechanism for novel treatments and providing quantitative links between inhibition and cognitive deficits which could improve the diagnosis of depression.