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CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X

Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encodin...

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Autores principales: Hwang, Jee-Yeon, Monday, Hannah R., Yan, Jingqi, Gompers, Andrea, Buxbaum, Adina R., Sawicka, Kirsty J., Singer, Robert H., Castillo, Pablo E., Zukin, R. Suzanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671216/
https://www.ncbi.nlm.nih.gov/pubmed/35675768
http://dx.doi.org/10.1016/j.celrep.2022.110853
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author Hwang, Jee-Yeon
Monday, Hannah R.
Yan, Jingqi
Gompers, Andrea
Buxbaum, Adina R.
Sawicka, Kirsty J.
Singer, Robert H.
Castillo, Pablo E.
Zukin, R. Suzanne
author_facet Hwang, Jee-Yeon
Monday, Hannah R.
Yan, Jingqi
Gompers, Andrea
Buxbaum, Adina R.
Sawicka, Kirsty J.
Singer, Robert H.
Castillo, Pablo E.
Zukin, R. Suzanne
author_sort Hwang, Jee-Yeon
collection PubMed
description Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription. We identify CPEB3, a protein implicated in memory consolidation, as an upstream effector critical to GluA2 mRNA expression in FXS. Increased GluA2 mRNA is translated into an increase in GluA2 subunits, a switch in synaptic AMPAR phenotype from GluA2-lacking, Ca(2+)-permeable to GluA2-containing, Ca(2+)-impermeable, reduced inhibitory synaptic transmission, and loss of NMDAR-independent LTP at glutamatergic synapses onto CA1 inhibitory interneurons. These factors could contribute to an excitatory/inhibitory imbalance—a common theme in FXS and other autism spectrum disorders.
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spelling pubmed-96712162022-11-17 CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X Hwang, Jee-Yeon Monday, Hannah R. Yan, Jingqi Gompers, Andrea Buxbaum, Adina R. Sawicka, Kirsty J. Singer, Robert H. Castillo, Pablo E. Zukin, R. Suzanne Cell Rep Article Fragile X syndrome (FXS) is a leading cause of inherited intellectual disability and autism. Whereas dysregulated RNA translation in Fmr1 knockout (KO) mice, a model of FXS, is well studied, little is known about aberrant transcription. Using single-molecule mRNA detection, we show that mRNA encoding the AMPAR subunit GluA2 (but not GluA1) is elevated in dendrites and at transcription sites of hippocampal neurons of Fmr1 KO mice, indicating elevated GluA2 transcription. We identify CPEB3, a protein implicated in memory consolidation, as an upstream effector critical to GluA2 mRNA expression in FXS. Increased GluA2 mRNA is translated into an increase in GluA2 subunits, a switch in synaptic AMPAR phenotype from GluA2-lacking, Ca(2+)-permeable to GluA2-containing, Ca(2+)-impermeable, reduced inhibitory synaptic transmission, and loss of NMDAR-independent LTP at glutamatergic synapses onto CA1 inhibitory interneurons. These factors could contribute to an excitatory/inhibitory imbalance—a common theme in FXS and other autism spectrum disorders. 2022-06-07 /pmc/articles/PMC9671216/ /pubmed/35675768 http://dx.doi.org/10.1016/j.celrep.2022.110853 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Hwang, Jee-Yeon
Monday, Hannah R.
Yan, Jingqi
Gompers, Andrea
Buxbaum, Adina R.
Sawicka, Kirsty J.
Singer, Robert H.
Castillo, Pablo E.
Zukin, R. Suzanne
CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X
title CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X
title_full CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X
title_fullStr CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X
title_full_unstemmed CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X
title_short CPEB3-dependent increase in GluA2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile X
title_sort cpeb3-dependent increase in glua2 subunits impairs excitatory transmission onto inhibitory interneurons in a mouse model of fragile x
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9671216/
https://www.ncbi.nlm.nih.gov/pubmed/35675768
http://dx.doi.org/10.1016/j.celrep.2022.110853
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