SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice-Reference-Cited by-同舟云学术

SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice

Published:2022-07-15 Issue:1 Volume:13 Page:
ISSN:2041-1723
Container-title:Nature Communications
language:en
Short-container-title:Nat Commun

Author:

El Chehadeh Salima^ORCID,Han Kyung Ah,Kim Dongwook,Jang Gyubin,Bakhtiari Somayeh,Lim Dongseok,Kim Hee Young,Kim Jinhu,Kim Hyeonho,Wynn Julia,Chung Wendy K.,Vitiello Giuseppina,Cutcutache Ioana,Page Matthew,Gecz Jozef^ORCID,Harper Kelly,Han Ah-reum,Kim Ho Min^ORCID,Wessels Marja,Bayat Allan^ORCID,Jaén Alberto Fernández^ORCID,Selicorni Angelo,Maitz Silvia,de Brouwer Arjan P. M.,Silfhout Anneke Vulto-van,Armstrong Martin,Symonds Joseph^ORCID,Küry Sébastien^ORCID,Isidor Bertrand,Cogné Benjamin^ORCID,Nizon Mathilde,Feger Claire,Muller Jean^ORCID,Torti Erin^ORCID,Grange Dorothy K.,Willems Marjolaine,Kruer Michael C.^ORCID,Ko Jaewon^ORCID,Piton Amélie^ORCID,Um Ji Won^ORCID

Abstract

AbstractSLITRK2 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.

Funder

National Research Foundation of Korea

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Link

https://www.nature.com/articles/s41467-022-31566-z.pdf

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