Asymmetric effects of activating and inactivating cortical interneurons

Bidirectional manipulations - activation and inactivation - are widely used to identify the functions supported by specific cortical interneuron types. Implicit in much of this work is the notion that tonic activation and inactivation will both produce valid, internally consistent insights into interneurons' computational roles. Here, using single-unit recordings in auditory cortex of awake mice, we show that this may not generally hold true. Optogenetically manipulating somatostatin-positive (Sst+) or parvalbumin-positive (Pvalb+) interneurons while recording tone-responses showed that Sst+ inactivation increased response gain, while Pvalb+ inactivation weakened tuning and decreased information transfer, implying that these neurons support delineable computational functions. But activating Sst+ and Pvalb+ interneurons revealed no such differences. We used a simple network model to understand this asymmetry, and showed how relatively small changes in key parameters, such as spontaneous activity or strength of the light manipulation, determined whether activation and inactivation would produce consistent or paradoxical conclusions regarding interneurons' computational functions.