Serotonin 5-HT Receptor Currents in the Healthy Rodent Prefrontal Cortex and in a Model of Affective Disorders

Affective disorders represent one of the greatest global burdens of disease. Work in patients with affective disorders demonstrates that serotonin (5-HT) signaling within the prefrontal cortex, particularly at the level of the 5-HT receptors, plays an integral role in both the pathology and treatment of these diseases. Surprisingly, the characterization of the prefrontal 5-HT receptors under both healthy and pathological conditions remains incomplete. The technique of whole cell electrophysiological recording provides an unparalleled tool for investigating the functional effects of these 5-HT receptors on neurons in acute prefrontal cortical slices. The objectives of my thesis were to delve deeper into the 5-HT receptor subtypes that modulate the prefrontal cortex in the healthy control rodents and to examine how this modulation was disrupted in a rodent model of affective disorders. In work from healthy control rodents, I examined two prefrontal 5-HT receptor-mediated currents. I show for the first time the presence of the 5-HT1A receptor during the early postnatal period, a critical developmental window during which this receptor programs adult anxiety behaviors. In adulthood, I characterized an inhibitory current mediated by the 5-ht5A receptor; findings that will permit the classification of this receptor within the 5-HT receptor family. Collectively, this investigation of functional early 5-HT1A receptors and adult 5-ht5A receptors offers a novel conceptual framework for understanding 5-HT receptor modulation of the healthy prefrontal cortex. To model vulnerability to affective disorder in the rodent, I used the early stress of maternal separation. In early stress rodents, I observed a marked increase in 5-HT1A receptor currents during the early postnatal period, the critical time window for the programming of anxiety. By comparison, in adulthood I found that rodents exposed to early stress displayed increased 5-HT2A receptor currents. These findings provide novel insight into the developmental and long-lasting pathology underlying early stress, indicating that the early prefrontal 5-HT1A receptor and adult prefrontal 5-HT2A receptors as a potential therapeutic target in treatment of affective disorders At a fundamental level, the findings provided herein offer critical insight into the cellular mechanisms underlying affective disorders, one of the most debilitating and costly diseases worldwide.Ph