Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome

Summary: Mutations of SHANK3 cause Phelan-McDermid syndrome (PMS), and these individuals can exhibit sensitivity to stress, resulting in behavioral deterioration. Here, we examine the interaction of stress with genotype using a mouse model with face validity to PMS. In Shank3ΔC/+ mice, swim stress p...

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Autores principales:	Raozhou Lin, Lisa N. Learman, M. Ali Bangash, Tatiana Melnikova, Erica Leyder, Sai C. Reddy, Nirinjini Naidoo, Joo Min Park, Alena Savonenko, Paul F. Worley
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Shank3 Homer1a stress autism Phelan-McDermid syndrome NMDAR Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8ae1f7981b914d949f9143310654f309
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spelling	oai:doaj.org-article:8ae1f7981b914d949f9143310654f3092021-11-18T04:47:56ZHomer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome2211-124710.1016/j.celrep.2021.110014https://doaj.org/article/8ae1f7981b914d949f9143310654f3092021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211124721014960https://doaj.org/toc/2211-1247Summary: Mutations of SHANK3 cause Phelan-McDermid syndrome (PMS), and these individuals can exhibit sensitivity to stress, resulting in behavioral deterioration. Here, we examine the interaction of stress with genotype using a mouse model with face validity to PMS. In Shank3ΔC/+ mice, swim stress produces an altered transcriptomic response in pyramidal neurons that impacts genes and pathways involved in synaptic function, signaling, and protein turnover. Homer1a, which is part of the Shank3-mGluR-N-methyl-D-aspartate (NMDA) receptor complex, is super-induced and is implicated in the stress response because stress-induced social deficits in Shank3ΔC/+ mice are mitigated in Shank3ΔC/+;Homer1a−/− mice. Several lines of evidence demonstrate that Shank3 expression is regulated by Homer1a in competition with crosslinking forms of Homer, and consistent with this model, Shank3 expression and function that are reduced in Shank3ΔC/+ mice are rescued in Shank3ΔC/+;Homer1a−/− mice. Studies highlight the interaction between stress and genetics and focus attention on activity-dependent changes that may contribute to pathogenesis.Raozhou LinLisa N. LearmanM. Ali BangashTatiana MelnikovaErica LeyderSai C. ReddyNirinjini NaidooJoo Min ParkAlena SavonenkoPaul F. WorleyElsevierarticleShank3Homer1astressautismPhelan-McDermid syndromeNMDARBiology (General)QH301-705.5ENCell Reports, Vol 37, Iss 7, Pp 110014- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Shank3 Homer1a stress autism Phelan-McDermid syndrome NMDAR Biology (General) QH301-705.5
spellingShingle	Shank3 Homer1a stress autism Phelan-McDermid syndrome NMDAR Biology (General) QH301-705.5 Raozhou Lin Lisa N. Learman M. Ali Bangash Tatiana Melnikova Erica Leyder Sai C. Reddy Nirinjini Naidoo Joo Min Park Alena Savonenko Paul F. Worley Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome
description	Summary: Mutations of SHANK3 cause Phelan-McDermid syndrome (PMS), and these individuals can exhibit sensitivity to stress, resulting in behavioral deterioration. Here, we examine the interaction of stress with genotype using a mouse model with face validity to PMS. In Shank3ΔC/+ mice, swim stress produces an altered transcriptomic response in pyramidal neurons that impacts genes and pathways involved in synaptic function, signaling, and protein turnover. Homer1a, which is part of the Shank3-mGluR-N-methyl-D-aspartate (NMDA) receptor complex, is super-induced and is implicated in the stress response because stress-induced social deficits in Shank3ΔC/+ mice are mitigated in Shank3ΔC/+;Homer1a−/− mice. Several lines of evidence demonstrate that Shank3 expression is regulated by Homer1a in competition with crosslinking forms of Homer, and consistent with this model, Shank3 expression and function that are reduced in Shank3ΔC/+ mice are rescued in Shank3ΔC/+;Homer1a−/− mice. Studies highlight the interaction between stress and genetics and focus attention on activity-dependent changes that may contribute to pathogenesis.
format	article
author	Raozhou Lin Lisa N. Learman M. Ali Bangash Tatiana Melnikova Erica Leyder Sai C. Reddy Nirinjini Naidoo Joo Min Park Alena Savonenko Paul F. Worley
author_facet	Raozhou Lin Lisa N. Learman M. Ali Bangash Tatiana Melnikova Erica Leyder Sai C. Reddy Nirinjini Naidoo Joo Min Park Alena Savonenko Paul F. Worley
author_sort	Raozhou Lin
title	Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome
title_short	Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome
title_full	Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome
title_fullStr	Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome
title_full_unstemmed	Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome
title_sort	homer1a regulates shank3 expression and underlies behavioral vulnerability to stress in a model of phelan-mcdermid syndrome
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/8ae1f7981b914d949f9143310654f309
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Homer1a regulates Shank3 expression and underlies behavioral vulnerability to stress in a model of Phelan-McDermid syndrome

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