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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH086033-02
Application #
8123205
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Desmond, Nancy L
Project Start
2010-08-15
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$231,660
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Neurosciences
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Robson, Matthew J; Zhu, Chong-Bin; Quinlan, Meagan A et al. (2016) Generation and Characterization of Mice Expressing a Conditional Allele of the Interleukin-1 Receptor Type 1. PLoS One 11:e0150068