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MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

Author(s): Nelson, PA; Sage, JR; Wood, SC; Davenport, CM; Anagnostaras, SG; et al

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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 suggestthat changes in MHCI expression could unexpectedly regulate neuronal insulin sensitivity in the aging and diseased brain.
Publication Date: 1-Sep-2013
Electronic Publication Date: 19-Aug-2013
Citation: Nelson, PA, Sage, JR, Wood, SC, Davenport, CM, Anagnostaras, SG, Boulanger, LM. (2013). MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression. Learning & Memory, 20 (9), 505 - 517. doi:10.1101/lm.031351.113
DOI: doi:10.1101/lm.031351.113
ISSN: 1072-0502
EISSN: 1549-5485
Pages: 1 - 13
Type of Material: Journal Article
Journal/Proceeding Title: The Journal of Neuroscience
Version: Final published version. Article is made available in OAR by the publisher's permission or policy.

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