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

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.

• Authors: Takashi Hayashi, Tomoyuki Yoshida, Moonjin Ra, Ryo Taguchi, Masayoshi Mishina
• Journal: PloS one (PLoS One) Vol. 8 Issue 6 Pg. e66254 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23785489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Autistic Disorder (genetics, metabolism)
• Carrier Proteins (metabolism)
• Cell Line
• Cerebral Cortex (cytology, metabolism)
• Gene Expression
• Gene Knockdown Techniques
• Glutamic Acid (metabolism)
• Humans
• Intellectual Disability (genetics, metabolism)
• Interleukin-1 Receptor Accessory Protein (chemistry, genetics, 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)