ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
MHC class I limits hippocampal synapse density by inhibiting neuronal insulin receptor signaling.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 55 citations in OpenAlex.
- The Cytoplasmic Domain of MHC Class I Molecules as a Molecular Switch: A Perspective from Short Linear Motifs and Intrinsically Disordered Regions.Biomolecules · 2026Review
- Intranasal Insulin Mitigates Memory Impairment and Neuroinflammation in a Mouse Model of Hippocampal Aging.Pharmacology research & perspectives · 2025Article
- An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Outside-in signaling through the major histocompatibility complex class-I cytoplasmic tail modulates glutamate receptor expression in neurons.Scientific reports · 2023Article
- The intracellular domain of major histocompatibility class-I proteins is essential for maintaining excitatory spine density and synaptic ultrastructure in the brain.Scientific reports · 2023Article
- Review
- Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa.Cell death & disease · 2022Article
- Homotypic and heterotypicCurrent research in immunology · 2022Review
- IL-1 reprogramming of adult neural stem cells limits neurocognitive recovery after viral encephalitis by maintaining a proinflammatory state.Brain, behavior, and immunity · 2022Article
- Hippocampal insulin resistance and the Sirtuin 1 signaling pathway in diabetes-induced cognitive dysfunction.Neural regeneration research · 2021Article
- Open MHC Class I Conformers: A Look through the Looking Glass.International journal of molecular sciences · 2021Review
- MHC class I H2-Kb negatively regulates neural progenitor cell proliferation by inhibiting FGFR signaling.PLoS biology · 2021Article
- Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer's disease.Molecular neurodegeneration · 2021Article
- Tight Regulation of Major Histocompatibility Complex I for the Spatial and Temporal Expression in the Hippocampal Neurons.Frontiers in cellular neuroscience · 2021Review
- CD45RA, CD8β, and IFNγ Are Potential Immune Biomarkers of Human Cognitive Function.Frontiers in immunology · 2020Article
- Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types.Frontiers in immunology · 2020Review
- Expression and Function of Zinc-α2-Glycoprotein.Neuroscience bulletin · 2019Review
- Severe Uncontrolled Maternal Hyperglycemia Induces Microsomia and Neurodevelopment Delay Accompanied by Apoptosis, Cellular Survival, and Neuroinflammatory Deregulation in Rat Offspring Hippocampus.Cellular and molecular neurobiology · 2019Article
- Insulin Peptides as Mediators of the Impact of Life Style in Alzheimer's disease.Brain plasticity (Amsterdam, Netherlands) · 2018Review
- Immunoglobulin-Like Receptors and Their Impact on Wiring of Brain Synapses.Annual review of genetics · 2018Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.