Control of Synapse Density by Major Histocompatibility Complex Class I Immune Proteins

Abstract

Appropriate connectivity in neural networks is established through the process of synapse elimination during development in vertebrates. The major histocompatibility complex class I (MHCI) is a large gene family encoding proteins which are best-known for their roles in the immune response. MHCI proteins have also been shown to limit synapse density in the visual system, cerebral cortex, and hippocampus. However, the molecular mechanism by which MHCI limits synapse density in the nervous system still remains unknown. I addressed this question in three different projects. First, I performed pharmacological and electron microscopic studies that indicate MHCI limits synapse density in the mouse hippocampus by inhibiting mTOR signaling. Second, I investigated which MHCIs might mediate MHCI’s effects on synapse elimination at the neuromuscular junction (NMJ). Previous work in the lab showed that mice deficient for cell-surface expression of most members of the large MHCI gene family have persistently impaired synapse elimination at the NMJ. To begin to define the specific MHCIs that are involved, MHCI mRNA expression patterns were profiled in three different muscles to identity the pool of MHCI genes that are expressed during development. Lastly, I investigated the molecular mechanisms by which MHCI inhibits the function of a glutamate receptor that is involved in synapse elimination in the central and peripheral nervous systems. Previous work in the lab indicated that MHCI inhibits N-methyl-D-aspartate receptor (NMDAR) function in the hippocampus, but the mechanisms remain unknown. I created a deletion construct of the MHCI cytoplasmic domain that is missing a C-terminal motif that could mediate interactions with NMDAR-regulatory proteins. This tool allowed us to test the role of this motif in proper NMDAR regulation.