Linking cortical inhibitory circuit dysfunction and psychiatric disease

Inhibitory interneurons make up approximately 10% of all cortical neurons, but they are critical for normal circuit functioning, as evidenced by the role of inhibitory dysfunction in a number of neurological and psychiatric diseases. In this dissertation, I show multiple examples of the role of inhibitory perturbations causing circuit dysfunction and abnormal behavior in models of psychiatric disease. In Chapter 1, I characterize behavioral abnormalities in a loss of function model of a high confidence autism gene, link these to changes in long-range communication between the prefrontal cortex and ventral hippocampus, and show deficits in inhibitory signaling related to these long-range deficits. In Chapter 2, I characterize the response of VIP interneurons to cholinergic stimulation and show this is altered in both genetic and environmental models of autism. In Chapter 3, I demonstrate how VIP interneuron signaling regulates prefrontal cortex-ventral hippocampal synchrony in order to properly regulate anxiety behavior. Together, these studies show how critical proper inhibitory signaling is to normal prefrontal cortex processing, and how disruptions in this signaling can give rise to disease states