Cited by 51Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

MHC class I limits hippocampal synapse density by inhibiting neuronal insulin receptor signaling

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Dixon-Salazar, Tracy J., Fourgeaud, Lawrence, Tyler, Carolyn M., Poole, Julianna R., Park, Joseph J., Boulanger, Lisa M.·2014·The Journal of Neuroscience

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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Crossref · 10.1523/jneurosci.4642-12.2014

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Authors
Dixon-Salazar, T. J., Fourgeaud, L., Tyler, C. M., Poole, J. R., Park, J. J., & Boulanger, L. M.
Affiliations
  • University of California San Diego (US)
  • Princeton University (US)
Venue
The Journal of Neuroscience
Published
2014-08-27
Volume
34
Issue
35
Pages
11844-11856
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W1989823625
Cited by
51
References
76
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 6 · 2015: 4 · 2014: 2
FWCI
2.74
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Mental Health (T32MH065214)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
MHC class I, insulin receptor signaling, synaptic density, hippocampus, dendritic spines, synaptic development, brain aging
MeSH terms
Animals, Hippocampus, Immunohistochemistry, Male, Mice, Inbred C57BL, Neurons, Organ Culture Techniques, Receptor, Insulin, Synapses, Blotting, Western, Histocompatibility Antigens Class I, Signal Transduction, Mice, Knockout, Microscopy, Electron, Transmission, Immunoprecipitation, Mice, Neurogenesis

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