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Articles, Cellular/Molecular

MHC Class I Limits Hippocampal Synapse Density by Inhibiting Neuronal Insulin Receptor Signaling

Tracy J. Dixon-Salazar, Lawrence Fourgeaud, Carolyn M. Tyler, Julianna R. Poole, Joseph J. Park and Lisa M. Boulanger
Journal of Neuroscience 27 August 2014, 34 (35) 11844-11856; DOI: https://doi.org/10.1523/JNEUROSCI.4642-12.2014
Tracy J. Dixon-Salazar
1Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093,
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Lawrence Fourgeaud
1Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093,
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Carolyn M. Tyler
2Department of Molecular Biology, and
3Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08540
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Julianna R. Poole
2Department of Molecular Biology, and
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Joseph J. Park
2Department of Molecular Biology, and
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Lisa M. Boulanger
1Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093,
2Department of Molecular Biology, and
3Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08540
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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 suggest that changes in MHCI expression could unexpectedly regulate neuronal insulin sensitivity in the aging and diseased brain.

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The Journal of Neuroscience: 34 (35)
Journal of Neuroscience
Vol. 34, Issue 35
27 Aug 2014
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MHC Class I Limits Hippocampal Synapse Density by Inhibiting Neuronal Insulin Receptor Signaling
Tracy J. Dixon-Salazar, Lawrence Fourgeaud, Carolyn M. Tyler, Julianna R. Poole, Joseph J. Park, Lisa M. Boulanger
Journal of Neuroscience 27 August 2014, 34 (35) 11844-11856; DOI: 10.1523/JNEUROSCI.4642-12.2014

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MHC Class I Limits Hippocampal Synapse Density by Inhibiting Neuronal Insulin Receptor Signaling
Tracy J. Dixon-Salazar, Lawrence Fourgeaud, Carolyn M. Tyler, Julianna R. Poole, Joseph J. Park, Lisa M. Boulanger
Journal of Neuroscience 27 August 2014, 34 (35) 11844-11856; DOI: 10.1523/JNEUROSCI.4642-12.2014
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