Mechanism and Synaptic Function of Binding Between Proteins Kirrel3 and IgSF8

Abstract Targeting and functional specificity of synapses rely on a complicated network of protein interactions. Trans- synaptic adhesion through cell surface proteins is one type of protein interaction that is required for synapse formation. Neurons express multiple synaptic cell surface proteins but little is known about how they interact with one another. This is important because many neurodevelopmental disorders are associated with altered surface protein expression. Kirrel3 is a cell surface and synaptic adhesion protein from the immunoglobulin superfamily and Kirrel3 is necessary to form mossy fiber filopodia synapses that connect dentate gyrus neurons to GABAergic neurons in the hippocampus. To elucidate the mechanism of Kirrel3 function at this synapse, I conducted a proteomic screen to identify Kirrel3 binding partners. One protein I identified is another Ig superfamily member called IgSF8. IgSF8 was also shown to be necessary for mossy fiber filopodia formation but how Kirrel3 and IgSF8 work together in constructing this synapse is unknown. In two aims, I will determine how Kirrel3 and IgSF8 physically interact and if the synaptogenic function of Kirrel3 depends on IgSF8. My results will advance the understanding of mechanisms by which synaptic specificity is achieved and given that Kirrel3 variants have been identified as risk factors for neurodevelopmental disorders, my results have potential to address a cellular foundation contributing to human disease.