Genetic and functional interactions between Itgb3 and Slc6a4 in mouse brain

Abstract

In the brain, serotonin (5-hydroxtryptamine, 5-HT) is synthesized in the raphe nucleus. Raphe serotonergic projections modulate neurotransmissions throughout the brain influencing mood and behavior. The serotonin transporter (SERT; SLC6A4) clears 5-HT from the synapse for degradation or reuse, thus regulating levels of 5-HT and limiting its actions on 5-HT receptors. Dysfunction in 5-HT modulation of neurotransmission is associated with mood and developmental disorders including anxiety, depression, and autism and there is genetic evidence for increased risk for depression in individuals possessing polymorphisms in SLC6A4 as well as genes which interact with SLC6A4. ITGB3 encodes integrin β3, a cell adhesion molecule which has been implicated as a modulator of peripheral serotonergic systems via genetic and functional interactions with SLC6A4, as well as in regulation of synaptic plasticity and maturation. In the brain, integrin β3 couples to integrin αv to form a functional receptor, making integrin αvβ3 an interesting target for regulation of neural 5-HT systems. Immunohistochemical experiments revealed integrin β3 localization in serotonergic neurons, colocalized with SERT. Examination of genetic interactions utilizing an Itgb3-/+ x Slc6a4-/+ mouse model revealed reduced SERT expression, and an anxiety- and depression-like phenotype compared to wildtype littermates. Further experimentation of the functional interaction between integrin αvβ3 and SERT via pharmacological targeting of integrin αvβ3 revealed integrin αvβ3 regulation of SERT uptake activity. These studies highlight integrin β3 as a potential modulator of brain 5-HT systems and subsequently 5-HT mediated behavioral phenotypes.