Synchronized, rhythmic activity within the prefrontal cortex (PFC) and at frequencies in the gamma range (~30- 120 Hz) is believed to contribute to many cognitive processes. A specific class of GABAergic interneurons (FSINs) that can be identified based either on their fast-spiking properties, or based on their expression of the calcium-binding protein parvalbumin (PV), play a critical role in these oscillations. Both prefrontal FSINs and gamma oscillations are abnormal in schizophrenia, suggesting that gamma oscillations may represent an important link between interneuron dysfunction and cognitive deficits; similar mechanisms may contribute to other neuropsychiatric disorders such as autism. Here, we will build on a recent study from our laboratory which found that stimulating interneurons at gamma frequencies can produce long-lasting improvements in cognitive flexibility in mice. Specifically, we studied mutant mice which model abnormalities in FSINs and gamma oscillations, as well as deficits in cognitive flexibility that are associated with schizophrenia. We found that using light sensitive proteins to active interneurons in the PFC at gamma frequencies enables these mice to perform normally on a task that measures cognitive flexibility. By contrast, activating these interneurons at other frequencies was ineffective. Now, we propose to explore whether activating PFC interneurons at gamma frequencies can enhance cognition in other contexts. For example, we will test whether activating PFC interneurons at gamma frequencies can rescue cognitive deficits in other mutant mice, in which interneuron function is not the sole or primary defect, or can produce supra-normal levels of performance in normal mice. We will also explore whether activating PFC interneurons at gamma frequencies can improve performance in tasks that measure other aspects of cognition, e.g. working memory. A second direction will be testing the idea that activating PFC interneurons at gamma-frequencies might enhance cognition by facilitating interactions between the PFC and other brain structures. In order to test this idea, we will measure how stimulating interneurons affects the degree to which activity in the PFC is synchronized with other structures. We will also determine whether activating PFC interneurons at gamma frequencies alters activity in other brain structures that are involved in cognitive flexibility. The long-term goal of this project is o determine whether enhancing interneuron-driven gamma oscillations in the PFC can improve cognitive deficits associated with schizophrenia and related disorders, and to identify possible mechanisms through which this might occur.