By 2011, the idea that the balance between excitation and inhibition (E/I balance) within neuronal circuits is altered in autism spectrum disorder (ASD), schizophrenia and related neuropsychiatric conditions had become familiar. This concept offered a way of bringing together diverse findings about genetic abnormalities, environmental stressors and psychiatric phenotypes, but it was still not obvious how the idea could be tested in a direct and mechanistic way. In their paper, Yizhar and colleagues approached that problem by asking whether an acute shift in E/I balance within a defined brain region would be sufficient to alter a behaviour with clear psychiatric relevance.

The authors focused on the medial prefrontal cortex and used a newly engineered stable step-function opsin to selectively increase the excitability of calcium/calmodulin-dependent protein kinase IIα (CaMKIIα)-positive pyramidal neurons or parvalbumin-positive interneurons in freely moving mice, allowing cell-type-specific manipulation of cellular E/I balance. This approach allowed the authors to avoid broad claims about ‘cortical imbalance’ and instead tie the discussion to a specific brain region, specific cell populations and a specific behavioural assay. The study also featured a well-judged emphasis on social behaviour, which the authors examined both as juvenile social exploration in the home cage and in the three-chamber social test. Social dysfunction is a central feature of several neuropsychiatric disorders, but it is often difficult to link such behavioural changes to specific circuit mechanisms. Here, its relationship to circuit physiology became much clearer.