Soluble Form of Lingo2, an Autism Spectrum Disorder-associated Molecule, Functions As an Excitatory Synapse Organizer in Neurons

Overview

Journal Transl Psychiatry

Specialties Psychiatry
Public Health

Date 2024 Oct 23

PMID 39443477

Authors

Fumiaki Yoshida

Ryota Nagatomo

Shun Utsunomiya

Misaki Kimura

Shiyori Shun

Rena Kono

Yuma Kato

Yosuke Nao

Kazuma Maeda

Ryuta Koyama

Yuji Ikegaya

Stefan F Lichtenthaler

Sho Takatori

Hiroshi Takemoto

Koichi Ogawa

Genta Ito

Taisuke Tomita

Affiliations

Soon will be listed here.

Abstract

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by impaired social communication and repetitive behaviors. In recent years, a pharmacological mouse model of ASD involving maternal administration of valproic acid (VPA) has become widely used. Newborn pups in this model show an abnormal balance between excitatory and inhibitory (E/I) signaling in neurons and exhibit ASD-like behavior. However, the molecular basis of this model and its implications for the pathogenesis of ASD in humans remain unknown. Using quantitative secretome analysis, we found that the level of leucine-rich repeat and immunoglobulin domain-containing protein 2 (Lingo2) was upregulated in the conditioned medium of VPA model neurons. This upregulation was associated with excitatory synaptic organizer activity. The secreted form of the extracellular domain of Lingo2 (sLingo2) is produced by the transmembrane metalloprotease ADAM10 through proteolytic processing. sLingo2 was found to induce the formation of excitatory synapses in both mouse and human neurons, and treatment with sLingo2 resulted in an increased frequency of miniature excitatory postsynaptic currents in human neurons. These findings suggest that sLingo2 is an excitatory synapse organizer involved in ASD, and further understanding of the mechanisms by which sLingo2 induces excitatory synaptogenesis is expected to advance our understanding of the pathogenesis of ASD.

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