title: MHC class I limits hippocampal synapse density by inhibiting neuronal insulin receptor signaling.
abstract: Proteins of the major histocompatibility complex class I (MHCI) negatively regulate synapse density in the developing vertebrate brain (Glynn et al., 2011; Elmer et al., 2013; Lee et al., 2014), but the underlying mechanisms remain largely unknown. Here we identify a novel MHCI signaling pathway that involves the inhibition of a known synapse-promoting factor, the insulin receptor. Dominant-negative insulin receptor constructs decrease synapse density in the developing Xenopus visual system (Chiu et al., 2008), and insulin receptor activation increases dendritic spine density in mouse hippocampal neurons in vitro (Lee et al., 2011). We find that genetically reducing cell surface MHCI levels increases synapse density selectively in regions of the hippocampus where insulin receptors are expressed, and occludes the neuronal insulin response by de-repressing insulin receptor signaling. Pharmacologically inhibiting insulin receptor signaling in MHCI-deficient animals rescues synapse density, identifying insulin receptor signaling as a critical mediator of the tonic inhibitory effects of endogenous MHCI on synapse number. Insulin receptors co-immunoprecipitate MHCI from hippocampal lysates, and MHCI unmasks a cytoplasmic epitope of the insulin receptor that mediates downstream signaling. These results identify an important role for an MHCI-insulin receptor signaling pathway in circuit patterning in the developing brain, and suggest that changes in MHCI expression could unexpectedly regulate neuronal insulin sensitivity in the aging and diseased brain.
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Dixon-Salazar
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fourgeaud
authors.affiliation: Department of Molecular Biology, and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08540.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Tyler
authors.affiliation: Department of Molecular Biology, and.
authors.forename: Julianna R
authors.initials: JR
authors.lastname: Poole
authors.affiliation: Department of Molecular Biology, and.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Park
authors.affiliation: Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, Department of Molecular Biology, and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08540 lboulang@princeton.edu.
authors.forename: Lisa M
authors.identifier: http://orcid.org/0000-0002-6578-7890
authors.initials: LM
authors.lastname: Boulanger
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D009924:Organ Culture Techniques; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D015395:Histocompatibility Antigens Class I; D011972:Receptor, Insulin