Dysfunction of the prefrontal cortex (PFC) contributes to cognitive deficits that represent the primary cause of disability associated with schizophrenia. However, currently available antipsychotic medications are only minimally effective for cognitive symptoms, demonstrating the need for better therapeutic targets. Treatments for cognitive deficits in schizophrenia remain underdeveloped in large part because the relevant physiological mechanisms remain unclear. A major hypothesis is that in schizophrenia, abnormalities in GABAergic interneurons, particularly fast- spiking interneurons (FSINs) that express parvalbumin (PV) and generate gamma (~30-120 Hz) oscillations, disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. To this end, we studied Dlx5/6+/- mice, which are deficient in transcription factors that regulate FSIN development, and found that abnormal FSIN development coincides with the onset of cognitive inflexibility and deficient task-evoked gamma oscillations. Strikingly, gamma-frequency optogenetic stimulation of PFC interneurons completely normalized cognitive flexibility in adult Dlx5/6+/- mice; inhibition of PFC interneurons in control mice reproduced cognitive inflexibility. These findings provide direct evidence for long hypothesized relationships between interneurons, gamma oscillations, and PFC-dependent cognition implicated in schizophrenia. My immediate goal is to characterize the circuit-specific activity dynamics of only PV interneurons during cognitive tasks in animals with intact and abnormal cognition. My long-term goals are to use these findings toward developing better-targeted treatments for schizophrenia. Under the mentorship of Drs. Vikaas Sohal and John Rubenstein, I will acquire the scientific and professional training necessary to address these goals and to succeed as an independent researcher. The outstanding resources, facilities, and multidisciplinary scientific community at UCSF are an ideal environment to ensure I realize my research and career objectives. My research plan is divided into four main aims: 1) to specifically target PV interneurons and define their role in cognitive flexibility, 2) to define th spatial and temporal activity patterns of PV interneurons in cognitive tasks, 3) to determine the role of long-range projections of PV interneurons in intact and abnormal cognition, and 4) to evaluate the effects of transplantation, a putative treatment. To achieve these aims, I will use a multidisciplinary approach, combining molecular biology, transgenics, fiber photometry, optogenetics, EEG, electrophysiology, and transplantation techniques. Through comparisons between intact and abnormal mouse models and this mechanistic link, we may finally be able to account for the behavioral phenotype in schizophrenia and devise novel therapeutic strategies for treating cognitive aspects of schizophrenia and related conditions.
Cognitive symptoms are the primary cause of disability associated with schizophrenia. Treatments for cognitive deficits in schizophrenia are underdeveloped because the relevant mechanisms remain unclear. Based on previous findings, this project investigates the role of a group of neurons, parvalbumin interneurons, whose dysfunction may result in cognitive impairments and focuses on the development of new treatments for this disorder.