IL1RAPL1 associated with mental retardation and autism regulates the formation and stabilization of glutamatergic synapses of cortical neurons through RhoA signaling pathway

PLoS One. 2013 Jun 13;8(6):e66254. doi: 10.1371/journal.pone.0066254. Print 2013.

Abstract

Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) is associated with X-linked mental retardation and autism spectrum disorder. We found that IL1RAPL1 regulates synapse formation of cortical neurons. To investigate how IL1RAPL1 controls synapse formation, we here screened IL1RAPL1-interacting proteins by affinity chromatography and mass spectroscopy. IL1RAPL1 interacted with Mcf2-like (Mcf2l), a Rho guanine nucleotide exchange factor, through the cytoplasmic Toll/IL-1 receptor domain. Knockdown of endogenous Mcf2l and treatment with an inhibitor of Rho-associated protein kinase (ROCK), the downstream kinase of RhoA, suppressed IL1RAPL1-induced excitatory synapse formation of cortical neurons. Furthermore, we found that the expression of IL1RAPL1 affected the turnover of AMPA receptor subunits. Insertion of GluA1-containing AMPA receptors to the cell surface was decreased, whereas that of AMPA receptors composed of GluA2/3 was enhanced. Mcf2l knockdown and ROCK inhibitor treatment diminished the IL1RAPL1-induced changes of AMPA receptor subunit insertions. Our results suggest that Mcf2l-RhoA-ROCK signaling pathway mediates IL1RAPL1-dependent formation and stabilization of glutamatergic synapses of cortical neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics
  • Autistic Disorder / metabolism*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Gene Expression
  • Gene Knockdown Techniques
  • Glutamic Acid / metabolism
  • Humans
  • Intellectual Disability / genetics
  • Intellectual Disability / metabolism*
  • Interleukin-1 Receptor Accessory Protein / chemistry
  • Interleukin-1 Receptor Accessory Protein / genetics
  • Interleukin-1 Receptor Accessory Protein / metabolism*
  • Mice
  • Neurons / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • RNA Interference
  • Receptors, AMPA / metabolism
  • Signal Transduction*
  • Synapses / metabolism*
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Carrier Proteins
  • Interleukin-1 Receptor Accessory Protein
  • Receptors, AMPA
  • interleukin-1 receptor accessory protein-like 1, mouse
  • Glutamic Acid
  • rhoA GTP-Binding Protein

Grant support

This work was supported in part by the Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Takeda Science Foundation, the Kanae Foundation for the Promotion of Medical Science, and Japan Science and Technology Agency. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.