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DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models
Down syndrome (DS) is caused by the trisomy of human chromosome 21 (HSA21). A major challenge in DS research is to identify the HSA21 genes that cause specific symptoms. Down syndrome cell adhesion molecule (DSCAM) is encoded by a HSA21 gene. Previous studies have shown that the protein level of the...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118173/ https://www.ncbi.nlm.nih.gov/pubmed/37079499 http://dx.doi.org/10.1371/journal.pbio.3002078 |
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author | Liu, Hao Caballero-Florán, René N. Hergenreder, Ty Yang, Tao Hull, Jacob M. Pan, Geng Li, Ruonan Veling, Macy W. Isom, Lori L. Kwan, Kenneth Y. Huang, Z. Josh Fuerst, Peter G. Jenkins, Paul M. Ye, Bing |
author_facet | Liu, Hao Caballero-Florán, René N. Hergenreder, Ty Yang, Tao Hull, Jacob M. Pan, Geng Li, Ruonan Veling, Macy W. Isom, Lori L. Kwan, Kenneth Y. Huang, Z. Josh Fuerst, Peter G. Jenkins, Paul M. Ye, Bing |
author_sort | Liu, Hao |
collection | PubMed |
description | Down syndrome (DS) is caused by the trisomy of human chromosome 21 (HSA21). A major challenge in DS research is to identify the HSA21 genes that cause specific symptoms. Down syndrome cell adhesion molecule (DSCAM) is encoded by a HSA21 gene. Previous studies have shown that the protein level of the Drosophila homolog of DSCAM determines the size of presynaptic terminals. However, whether the triplication of DSCAM contributes to presynaptic development in DS remains unknown. Here, we show that DSCAM levels regulate GABAergic synapses formed on neocortical pyramidal neurons (PyNs). In the Ts65Dn mouse model for DS, where DSCAM is overexpressed due to DSCAM triplication, GABAergic innervation of PyNs by basket and chandelier interneurons is increased. Genetic normalization of DSCAM expression rescues the excessive GABAergic innervations and the increased inhibition of PyNs. Conversely, loss of DSCAM impairs GABAergic synapse development and function. These findings demonstrate excessive GABAergic innervation and synaptic transmission in the neocortex of DS mouse models and identify DSCAM overexpression as the cause. They also implicate dysregulated DSCAM levels as a potential pathogenic driver in related neurological disorders. |
format | Online Article Text |
id | pubmed-10118173 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-101181732023-04-21 DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models Liu, Hao Caballero-Florán, René N. Hergenreder, Ty Yang, Tao Hull, Jacob M. Pan, Geng Li, Ruonan Veling, Macy W. Isom, Lori L. Kwan, Kenneth Y. Huang, Z. Josh Fuerst, Peter G. Jenkins, Paul M. Ye, Bing PLoS Biol Research Article Down syndrome (DS) is caused by the trisomy of human chromosome 21 (HSA21). A major challenge in DS research is to identify the HSA21 genes that cause specific symptoms. Down syndrome cell adhesion molecule (DSCAM) is encoded by a HSA21 gene. Previous studies have shown that the protein level of the Drosophila homolog of DSCAM determines the size of presynaptic terminals. However, whether the triplication of DSCAM contributes to presynaptic development in DS remains unknown. Here, we show that DSCAM levels regulate GABAergic synapses formed on neocortical pyramidal neurons (PyNs). In the Ts65Dn mouse model for DS, where DSCAM is overexpressed due to DSCAM triplication, GABAergic innervation of PyNs by basket and chandelier interneurons is increased. Genetic normalization of DSCAM expression rescues the excessive GABAergic innervations and the increased inhibition of PyNs. Conversely, loss of DSCAM impairs GABAergic synapse development and function. These findings demonstrate excessive GABAergic innervation and synaptic transmission in the neocortex of DS mouse models and identify DSCAM overexpression as the cause. They also implicate dysregulated DSCAM levels as a potential pathogenic driver in related neurological disorders. Public Library of Science 2023-04-20 /pmc/articles/PMC10118173/ /pubmed/37079499 http://dx.doi.org/10.1371/journal.pbio.3002078 Text en © 2023 Liu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Liu, Hao Caballero-Florán, René N. Hergenreder, Ty Yang, Tao Hull, Jacob M. Pan, Geng Li, Ruonan Veling, Macy W. Isom, Lori L. Kwan, Kenneth Y. Huang, Z. Josh Fuerst, Peter G. Jenkins, Paul M. Ye, Bing DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models |
title | DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models |
title_full | DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models |
title_fullStr | DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models |
title_full_unstemmed | DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models |
title_short | DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models |
title_sort | dscam gene triplication causes excessive gabaergic synapses in the neocortex in down syndrome mouse models |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118173/ https://www.ncbi.nlm.nih.gov/pubmed/37079499 http://dx.doi.org/10.1371/journal.pbio.3002078 |
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