SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 07 2022
15 07 2022
Historique:
received:
17
09
2021
accepted:
22
06
2022
entrez:
15
7
2022
pubmed:
16
7
2022
medline:
20
7
2022
Statut:
epublish
Résumé
SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function.
Identifiants
pubmed: 35840571
doi: 10.1038/s41467-022-31566-z
pii: 10.1038/s41467-022-31566-z
pmc: PMC9287327
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4112Subventions
Organisme : NINDS NIH HHS
ID : R01 NS106298
Pays : United States
Informations de copyright
© 2022. The Author(s).
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