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Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors

We previously reported a new line of Shank3 mutant mice which led to a complete loss of Shank3 by deleting exons 4−22 (Δe4−22) globally. Δe4−22 mice display robust ASD-like behaviors including impaired social interaction and communication, increased stereotypical behavior and excessive grooming, and...

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Autores principales: Bey, Alexandra L., Wang, Xiaoming, Yan, Haidun, Kim, Namsoo, Passman, Rebecca L., Yang, Yilin, Cao, Xinyu, Towers, Aaron J., Hulbert, Samuel W., Duffney, Lara J., Gaidis, Erin, Rodriguiz, Ramona M., Wetsel, William C., Yin, Henry H., Jiang, Yong-hui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919902/
https://www.ncbi.nlm.nih.gov/pubmed/29700290
http://dx.doi.org/10.1038/s41398-018-0142-6
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author Bey, Alexandra L.
Wang, Xiaoming
Yan, Haidun
Kim, Namsoo
Passman, Rebecca L.
Yang, Yilin
Cao, Xinyu
Towers, Aaron J.
Hulbert, Samuel W.
Duffney, Lara J.
Gaidis, Erin
Rodriguiz, Ramona M.
Wetsel, William C.
Yin, Henry H.
Jiang, Yong-hui
author_facet Bey, Alexandra L.
Wang, Xiaoming
Yan, Haidun
Kim, Namsoo
Passman, Rebecca L.
Yang, Yilin
Cao, Xinyu
Towers, Aaron J.
Hulbert, Samuel W.
Duffney, Lara J.
Gaidis, Erin
Rodriguiz, Ramona M.
Wetsel, William C.
Yin, Henry H.
Jiang, Yong-hui
author_sort Bey, Alexandra L.
collection PubMed
description We previously reported a new line of Shank3 mutant mice which led to a complete loss of Shank3 by deleting exons 4−22 (Δe4−22) globally. Δe4−22 mice display robust ASD-like behaviors including impaired social interaction and communication, increased stereotypical behavior and excessive grooming, and a profound deficit in instrumental learning. However, the anatomical and neural circuitry underlying these behaviors are unknown. We generated mice with Shank3 selectively deleted in forebrain, striatum, and striatal D1 and D2 cells. These mice were used to interrogate the circuit/brain-region and cell-type specific role of Shank3 in the expression of autism-related behaviors. Whole-cell patch recording and biochemical analyses were used to study the synaptic function and molecular changes in specific brain regions. We found perseverative exploratory behaviors in mice with deletion of Shank3 in striatal inhibitory neurons. Conversely, self-grooming induced lesions were observed in mice with deletion of Shank3 in excitatory neurons of forebrain. However, social, communicative, and instrumental learning behaviors were largely unaffected in these mice, unlike what is seen in global Δe4−22 mice. We discovered unique patterns of change for the biochemical and electrophysiological findings in respective brain regions that reflect the complex nature of transcriptional regulation of Shank3. Reductions in Homer1b/c and membrane hyper-excitability were observed in striatal loss of Shank3. By comparison, Shank3 deletion in hippocampal neurons resulted in increased NMDAR-currents and GluN2B-containing NMDARs. These results together suggest that Shank3 may differentially regulate neural circuits that control behavior. Our study supports a dissociation of Shank3 functions in cortical and striatal neurons in ASD-related behaviors, and it illustrates the complexity of neural circuit mechanisms underlying these behaviors.
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spelling pubmed-59199022018-04-27 Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors Bey, Alexandra L. Wang, Xiaoming Yan, Haidun Kim, Namsoo Passman, Rebecca L. Yang, Yilin Cao, Xinyu Towers, Aaron J. Hulbert, Samuel W. Duffney, Lara J. Gaidis, Erin Rodriguiz, Ramona M. Wetsel, William C. Yin, Henry H. Jiang, Yong-hui Transl Psychiatry Article We previously reported a new line of Shank3 mutant mice which led to a complete loss of Shank3 by deleting exons 4−22 (Δe4−22) globally. Δe4−22 mice display robust ASD-like behaviors including impaired social interaction and communication, increased stereotypical behavior and excessive grooming, and a profound deficit in instrumental learning. However, the anatomical and neural circuitry underlying these behaviors are unknown. We generated mice with Shank3 selectively deleted in forebrain, striatum, and striatal D1 and D2 cells. These mice were used to interrogate the circuit/brain-region and cell-type specific role of Shank3 in the expression of autism-related behaviors. Whole-cell patch recording and biochemical analyses were used to study the synaptic function and molecular changes in specific brain regions. We found perseverative exploratory behaviors in mice with deletion of Shank3 in striatal inhibitory neurons. Conversely, self-grooming induced lesions were observed in mice with deletion of Shank3 in excitatory neurons of forebrain. However, social, communicative, and instrumental learning behaviors were largely unaffected in these mice, unlike what is seen in global Δe4−22 mice. We discovered unique patterns of change for the biochemical and electrophysiological findings in respective brain regions that reflect the complex nature of transcriptional regulation of Shank3. Reductions in Homer1b/c and membrane hyper-excitability were observed in striatal loss of Shank3. By comparison, Shank3 deletion in hippocampal neurons resulted in increased NMDAR-currents and GluN2B-containing NMDARs. These results together suggest that Shank3 may differentially regulate neural circuits that control behavior. Our study supports a dissociation of Shank3 functions in cortical and striatal neurons in ASD-related behaviors, and it illustrates the complexity of neural circuit mechanisms underlying these behaviors. Nature Publishing Group UK 2018-04-27 /pmc/articles/PMC5919902/ /pubmed/29700290 http://dx.doi.org/10.1038/s41398-018-0142-6 Text en © The Author(s) 2018 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/.
spellingShingle Article
Bey, Alexandra L.
Wang, Xiaoming
Yan, Haidun
Kim, Namsoo
Passman, Rebecca L.
Yang, Yilin
Cao, Xinyu
Towers, Aaron J.
Hulbert, Samuel W.
Duffney, Lara J.
Gaidis, Erin
Rodriguiz, Ramona M.
Wetsel, William C.
Yin, Henry H.
Jiang, Yong-hui
Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
title Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
title_full Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
title_fullStr Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
title_full_unstemmed Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
title_short Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
title_sort brain region-specific disruption of shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919902/
https://www.ncbi.nlm.nih.gov/pubmed/29700290
http://dx.doi.org/10.1038/s41398-018-0142-6
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