Format

Send to

Choose Destination
See comment in PubMed Commons below
J Neurosci. 2014 Aug 27;34(35):11844-56. doi: 10.1523/JNEUROSCI.4642-12.2014.

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

Author information

  • 1Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093.
  • 2Department of Molecular Biology, and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08540.
  • 3Department of Molecular Biology, and.
  • 4Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, Department of Molecular Biology, and Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08540 lboulang@princeton.edu.

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.

PMID:
25164678
PMCID:
PMC4468138
DOI:
10.1523/JNEUROSCI.4642-12.2014
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center