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

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dc.contributor.authorEl Chehadeh, S.
dc.contributor.authorHan, K.A.
dc.contributor.authorKim, D.
dc.contributor.authorJang, G.
dc.contributor.authorBakhtiari, S.
dc.contributor.authorLim, D.
dc.contributor.authorKim, H.Y.
dc.contributor.authorKim, J.
dc.contributor.authorKim, H.
dc.contributor.authorWynn, J.
dc.contributor.authorChung, W.K.
dc.contributor.authorVitiello, G.
dc.contributor.authorCutcutache, I.
dc.contributor.authorPage, M.
dc.contributor.authorGecz, J.
dc.contributor.authorHarper, K.
dc.contributor.authorHan, A.-R.
dc.contributor.authorKim, H.M.
dc.contributor.authorWessels, M.
dc.contributor.authorBayat, A.
dc.contributor.authoret al.
dc.date.issued2022
dc.description.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.
dc.identifier.citationNature Communications, 2022; 13(1):4112-1-4112-19
dc.identifier.doi10.1038/s41467-022-31566-z
dc.identifier.issn2041-1723
dc.identifier.issn2041-1723
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttps://hdl.handle.net/2440/146079
dc.language.isoen
dc.publisherNature Portfolio
dc.rights© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41467-022-31566-z
dc.subjectAutism spectrum disorders; Neural circuits; Neurotransmitters
dc.subject.meshHippocampus
dc.subject.meshSynapses
dc.subject.meshAnimals
dc.subject.meshMice, Knockout
dc.subject.meshMice
dc.subject.meshCognition
dc.subject.meshNeurodevelopmental Disorders
dc.titleSLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.
dc.typeJournal article
pubs.publication-statusPublished

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