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Sex-dependent role for EPHB2 in brain development and autism-associated behavior
Autism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A d...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429442/ https://www.ncbi.nlm.nih.gov/pubmed/33649502 http://dx.doi.org/10.1038/s41386-021-00986-8 |
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author | Assali, Ahlem Cho, Jennifer Y. Tsvetkov, Evgeny Gupta, Abha R. Cowan, Christopher W. |
author_facet | Assali, Ahlem Cho, Jennifer Y. Tsvetkov, Evgeny Gupta, Abha R. Cowan, Christopher W. |
author_sort | Assali, Ahlem |
collection | PubMed |
description | Autism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2(+/−)) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2(+/−) female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2(+/−) female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice. |
format | Online Article Text |
id | pubmed-8429442 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-84294422021-09-14 Sex-dependent role for EPHB2 in brain development and autism-associated behavior Assali, Ahlem Cho, Jennifer Y. Tsvetkov, Evgeny Gupta, Abha R. Cowan, Christopher W. Neuropsychopharmacology Article Autism spectrum disorder (ASD) is characterized by impairments in social communication and interaction and restricted, repetitive behaviors. It is frequently associated with comorbidities, such as attention-deficit hyperactivity disorder, altered sensory sensitivity, and intellectual disability. A de novo nonsense mutation in EPHB2 (Q857X) was discovered in a female patient with ASD [13], revealing EPHB2 as a candidate ASD risk gene. EPHB2 is a receptor tyrosine kinase implicated in axon guidance, synaptogenesis, and synaptic plasticity, positioning it as a plausible contributor to the pathophysiology of ASD and related disorders. In this study, we show that the Q857X mutation produced a truncated protein lacking forward signaling and that global disruption of one EphB2 allele (EphB2(+/−)) in mice produced several behavioral phenotypes reminiscent of ASD and common associated symptoms. EphB2(+/−) female, but not male, mice displayed increased repetitive behavior, motor hyperactivity, and learning and memory deficits, revealing sex-specific effects of EPHB2 hypofunction. Moreover, we observed a significant increase in the intrinsic excitability, but not excitatory/inhibitory ratio, of motor cortex layer V pyramidal neurons in EphB2(+/−) female, but not male, mice, suggesting a possible mechanism by which EPHB2 hypofunction may contribute to sex-specific motor-related phenotypes. Together, our findings suggest that EPHB2 hypofunction, particularly in females, is sufficient to produce ASD-associated behaviors and altered cortical functions in mice. Springer International Publishing 2021-03-01 2021-10 /pmc/articles/PMC8429442/ /pubmed/33649502 http://dx.doi.org/10.1038/s41386-021-00986-8 Text en © The Author(s), under exclusive licence to American College of Neuropsychopharmacology 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Assali, Ahlem Cho, Jennifer Y. Tsvetkov, Evgeny Gupta, Abha R. Cowan, Christopher W. Sex-dependent role for EPHB2 in brain development and autism-associated behavior |
title | Sex-dependent role for EPHB2 in brain development and autism-associated behavior |
title_full | Sex-dependent role for EPHB2 in brain development and autism-associated behavior |
title_fullStr | Sex-dependent role for EPHB2 in brain development and autism-associated behavior |
title_full_unstemmed | Sex-dependent role for EPHB2 in brain development and autism-associated behavior |
title_short | Sex-dependent role for EPHB2 in brain development and autism-associated behavior |
title_sort | sex-dependent role for ephb2 in brain development and autism-associated behavior |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429442/ https://www.ncbi.nlm.nih.gov/pubmed/33649502 http://dx.doi.org/10.1038/s41386-021-00986-8 |
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