Soluble form of Lingo2, an autism spectrum disorder-associated molecule, functions as an excitatory synapse organizer in neurons.
Autism Spectrum Disorder
/ metabolism
Animals
Humans
Neurons
/ metabolism
Mice
Nerve Tissue Proteins
/ metabolism
Synapses
/ metabolism
Membrane Proteins
/ metabolism
Disease Models, Animal
Excitatory Postsynaptic Potentials
/ drug effects
Valproic Acid
/ pharmacology
Mice, Inbred C57BL
Female
ADAM10 Protein
/ metabolism
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
23 Oct 2024
23 Oct 2024
Historique:
received:
28
09
2024
accepted:
15
10
2024
revised:
13
10
2024
medline:
24
10
2024
pubmed:
24
10
2024
entrez:
23
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39443477
doi: 10.1038/s41398-024-03167-5
pii: 10.1038/s41398-024-03167-5
doi:
Substances chimiques
Nerve Tissue Proteins
0
Membrane Proteins
0
Valproic Acid
614OI1Z5WI
ADAM10 Protein
EC 3.4.24.81
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
448Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 15H02492
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 19H01015
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 23H00394
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 20K21471
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 19J14908
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 22K21353
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 390857198
Organisme : MEXT | Japan Science and Technology Agency (JST)
ID : JPMJER1801
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : 22g1510002h0002
Informations de copyright
© 2024. The Author(s).
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