Interleukin-1 (IL-1) Receptor-Mediated Modulation of Serotonin Transporters

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DESCRIPTION (provided by applicant): The role of pro-inflammatory cytokines in the pathogenesis of neuropsychiatric disorders has drawn a significant interest over the last decade. Cytokines are also known to modulate serotonergic activity. The 5-HT transporter (SERT), one of the major targets of antidepressants, which supports 5-HT inactivation and recycling, is tightly regulated by multiple signaling pathways including those stimulated by the proinflammatory cytokines IL-1¿ and TNF-a. We have shown that IL-1¿ stimulates SERT activity in a raphe cell line as well as in mouse synaptosomes ex vivo. Our preliminary data now demonstrate that peripheral injection of LPS induces an acute (1hr) increase in central 5-HT uptake in wild type mice but not in IL-1R knockouts. We hypothesizes that a presynaptic IL-1Rs communicates local and systemic inflammatory stress (and other stressors) via modulation of SERT activity. As the distribution of IL-1Rs in the CNS is not limited to the raphe neurons and their terminals, dissecting the contribution of serotonergic modulation will require restricted elimination of IL-1¿ action. Thus, the objectives of the current proposal are to generate IL-1R floxed mice, further develop serotonergic neuron specific IL-1R knockout using FloxP/Cre technologies and to characterize the 5-HT homeostasis and related behaviors in these animals. My hypothesis is that deletion of IL-1 receptors in the raphe serotonergic neurons will eliminate the impact of IL-1¿ / LPS on central SERT activity. The validation of this hypothesis will (1) provide critical data for an enlarged study examining cytokine-5HT interactions and (2) help to advance our understanding towards the contribution of modulated 5HT signaling networks to depression-like traits that emerge in sickness syndrome paradigms. To achieve the goal of this proposal, we plan to conduct the following studies: 1. Generate floxed IL-1R mice; 2 Develop and characterize serotonergic neuron-specific IL-1R knockout mice. The essential goal of this project is to achieve germ-line transmission of a floxed allele of the IL-1R with no inherent impact on native IL-1R production in the absence of a Cre driver, and eventually develop conditional IL-1R knockouts. Together, these efforts support the long-term goal of elucidating in vivo mechanisms through which pro-inflammatory cytokines modulate brain function and behavior. PUBLIC HEALTH RELEVANCE: This project investigates the link between Immunological challenges and a key gene controlling the neurotransmitter serotonin for insights into mechanisms that may impact risk for mood disorders including depression, anxiety and autism. This project specifically investigates the immune mediator Interleukin-1 and its receptor in regulation of the brain serotonin transporter (SERT), a major target for antidepressant medications. These studies seek to develop a novel transgenic mouse model that can address the sensitivity of brain serotonin neurons and SERT to IL-1¿ and establish an experimental framework to more precisely link the immune system to mood regulatory mechanisms.