MHC class I limits hippocampal synapse density by inhibiting neuronal insulin receptor signaling
Open accessAbstract
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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H2-K and H2-D negatively regulate dendritic complexity and the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal and cortical neurons.
“H2-K and H2-D also negatively regulate dendritic complexity and the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal and cortical neurons”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [26]
H2-K and H2-D limit the levels of Ca2+-permeable AMPA receptors in the lateral geniculate nucleus.
“limit the levels of Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the lateral geniculate nucleus.21,22,26,27,28,29”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [26]
A growing number of immune proteins have been identified that play central roles in neuronal homeostasis, where they negatively regulate neurite length, dendritic complexity, and synaptic transmission, and many are upregulated by TLR9.
“A growing number of immune proteins have been identified that play central roles in neuronal homeostasis, where they negatively regulate neurite length, dendritic complexity, and synaptic transmission,20,21,22,23,24,25,26,27,28,29,45,46,48,72,73,74,75,76,77,78,79 and many are upregulated by TLR9.”
From An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission (2024) · cites this paper as [26]
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RetractedCardoso, E. M., Lourenço‐Gomes, V., Esgalhado, A. J., Reste‐Ferreira, D., Oliveira, N., Amaral, A. S., Martinho, A., Gama, J. M. R., Verde, I., Lourenço, O. M., et al. (2023) · HLA · doi:10.1111/tan.15149 · Cited by 5 · see citing works
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Arosa, F. A., & Cardoso, E. M. (2026) · Biomolecules · doi:10.3390/biom16071067
- 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
- Publisher
- Society for Neuroscience
- Published
- 2014-08-27
- Volume
- 34
- Issue
- 35
- Pages
- 11844-11856
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4468138
- 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
- hybrid
- doi.org
- Licence
- 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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