The prefrontal 5-HT7 receptor as a therapeutic target in psychiatric disorders including anxiety and depression

Maternal separation (MS) during the early postnatal period (P2–14) is a well-established model of early-life stress that induces persistent alterations in prefrontal cortical circuits and increases susceptibility to anxiety and depressive-like behaviors in adulthood. Previous studies from our laboratory identified the serotonin 5-HT7 receptor as a key mediator of these long-term effects. We hypothesize that 5-HT7 receptors expressed by glutamatergic neurons in the prefrontal cortex critically contribute to the maladaptive development of the prefrontal cortex–dorsal raphe nucleus (PFC–DRN) circuit following early-life stress. As a first step, we are validating an AAV-mediated short hairpin RNA (shRNA) targeting the last exon shared by all 5-HT7 receptor transcript variants in primary cultures of mouse cortical neurons. The ultimate goal is to design a miRNA targeting this receptor mRNA delivered selectively to glutamatergic neurons. We will assess PFC–DRN synaptic connectivity using high-resolution microscopy and evaluate anxiety and depressive-like behaviors in adulthood. This approach will determine whether selective early reduction of 5-HT7 expression in prefrontal glutamatergic neurons is sufficient to prevent the long-term neural and behavioral consequences of early-life stress.