Impact of developmental serotonin on prefrontal cortex parvalbumin interneuron excitability and cognitive behavior

PROJECT SUMMARY/ABSTRACT Sensitive periods are periods during early windows of development in external experiences or exposures can shape patterns of connectivity and behavior later in life. Such periods allow for circuit maturation to adapt to environmental factors but also confer risk for psychiatric disorders. Indeed, previous work in our lab has shown that suppressing the activity of prefrontal parvalbumin-expressing (PFC PV) interneurons during postnatal day 14 to 32 (P14-P32) results in impaired neural connectivity, network function and PFC-dependent cognitive flexibility later in life. Cognitive inflexibility and PFC dysfunction are both hallmarks of various psychiatric illnesses, whose origins are often rooted in development. Thus, it is pivotal to understand the factors that influence the activity of developing PFC PV interneurons, leading to alterations in PFC circuit remodeling. The neuromodulator serotonin (5-HT) is well positioned to influence the activity of developing PFC PV cells. Indeed, the PFC is densely innervated by 5-HT and 5-HT receptors can be detected in the developing PFC. Additionally, 5-HT modulates PFC PV activity in adulthood. Moreover, 5-HT release in development, which can be caused various external and genetic factors, versus adulthood yields opposing effects on adult cognition. For instance, increases in 5-HT release into the PFC in adulthood improves cognitive flexibility, and I have demonstrated that potentiating 5-HT release in development (P12-21) impairs adult cognitive flexibility. I hypothesize that P14-21 is a sensitive period during which potentiating 5-HT signaling may suppress PV excitability with long-lasting consequences for cognitive behavior. My experiments are designed to elucidate mechanisms contributing to the developmental trajectories of complex cognitive behavior and identify early risk factors of mental illness. In Aim 1, I investigate the direct effects of 5-HT on developing PFC PV excitability by employing slice electrophysiology. In Aim 2, I examine the net effects of 5-HT release into the PFC on PV interneuron activity using an in vivo model, optogenetics and fiber photometry. With these experiments, I will test the hypothesis that 5-HT release during development suppresses the activity of PFC PV interneurons and shifts into exciting PV in adulthood. In Aim 3, I evaluate how 5-HT potentiation to the PFC alters cognitive flexibility using chemogenetics and cognitive flexibility assays. With this experiment, I will test the hypothesis that developmental potentiation 5-HT release into the PFC is sufficient and necessary to produce cognitive inflexibility. Overall, my goal for this proposal is to better understand how factors that affect 5-HT levels impact PFC development and PFC-dependent cognitive behavior later in life. As PV interneurons are critical for PFC maturation, their interactions with 5-HT may constitute important markers preceding the onset of disease.