Cholecystokinin-expressing Interneurons of the Medial Prefrontal Cortex Mediate Working Memory Retrieval

Distinct components of working memory are co-ordinated by different classes of inhibitory interneurons in the prefrontal cortex, but the role of CCK-positive interneurons remains enigmatic. In humans, this major population of interneurons shows histological abnormalities in schizophrenia, an illness in which deficient working memory is a core defining symptom and the best predictor of long-term functional outcome. Yet, CCK interneurons as a molecularly distinct class have proved intractable to examination by typical molecular methods due to widespread expression of CCK in the pyramidal neuron population. Using an intersectional approach in mice of both sexes, we have succeeded in labeling, interrogating, and manipulating CCK interneurons in the medial prefrontal cortex. Here, we describe the anatomical distribution, electrophysiological properties, and postsynaptic connectivity of CCK interneurons, and evaluate their role in cognition. We found that CCK interneurons comprise a larger proportion of the mPFC interneurons compared to PV interneurons, targeting a wide range of neuronal subtypes with a distinct connectivity pattern. Phase-specific optogenetic inhibition revealed that CCK, but not PV, interneurons play a critical role in the retrieval of working memory. These findings shine new light on the relationship between cortical CCK interneurons and cognition and offer a new set of tools to investigate interneuron dysfunction and cognitive impairments associated with schizophrenia. SIGNIFICANCE STATEMENT Cholecystokinin (CCK)-expressing interneurons outnumber other interneuron populations in key brain areas involved in cognition and memory, including the medial prefrontal cortex (mPFC). However, they have proved intractable to examination as experimental techniques have lacked the necessary selectivity. To the best of our knowledge, the present study is the first to report detailed properties of cortical CCK interneurons, revealing their anatomical organization, electrophysiological properties, postsynaptic connectivity, and behavioural function in working memory.