PROJECT SUMMARY Social behavior comprises multiple distinct types of interactions that play a critical role in reproduction, survival, and over-all well-being. Dysfunction of the serotonin system has long been associated with social deficits present in a host of psychiatric and neurodevelopmental disorders, including depression, anxiety, schizophrenia, and autism spectrum disorders. It is therefore not surprising that therapeutics targeting the serotonin system, such as selective serotonin reuptake inhibitors (SSRIs), are commonly prescribed. Unfortunately, they are often ineffective in improving deficits in social behavior. Accumulating evidence supports the notion that alterations in chromatin remodelers and transcription factors play a critical role in the development of a host of disorders. Recent findings demonstrate that selective deletion of the chromatin remodeling subunit, Arid1b, in serotoninergic neurons results in social deficits in mice. Interestingly, rapid elevation of serotonin levels enhances sociability and promotes appropriate social behavior. These findings suggest that the speed and degree of serotonin enhancement is a critical regulator of its therapeutic effects. Think of the cooling effects of using a folding fan on a humid summer day in comparison to that of having central air conditioning on full blast. This analogy illustrates the difference in serotonin elevation due to SSRIs versus the potent serotonin releaser MDMA, used in our studies. Unfortunately, this effect is only temporary, and deficits resume when serotonin levels return to baseline. However, our preliminary data suggests that a simple 2-dose MDMA regimen can cause lasting increases in sociability in mice with this genetic deletion. The goal of this project is to identify the circuit, cellular, and molecular adaptations underlying this potential groundbreaking therapeutic phenomenon. By studying the neural mechanisms underlying sociability, we aim to shed light on a critically important element of the human experience, suggesting a novel approach to effective treatments for this devastating component of many neuropsychiatric disorders.