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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-04-01
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| Series: | PLoS Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118173/?tool=EBI |
| _version_ | 1797839945713319936 |
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| author | Hao Liu René N. Caballero-Florán Ty Hergenreder Tao Yang Jacob M. Hull Geng Pan Ruonan Li Macy W. Veling Lori L. Isom Kenneth Y. Kwan Z. Josh Huang Peter G. Fuerst Paul M. Jenkins Bing Ye |
| author_facet | Hao Liu René N. Caballero-Florán Ty Hergenreder Tao Yang Jacob M. Hull Geng Pan Ruonan Li Macy W. Veling Lori L. Isom Kenneth Y. Kwan Z. Josh Huang Peter G. Fuerst Paul M. Jenkins Bing Ye |
| author_sort | Hao Liu |
| collection | DOAJ |
| 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. Developmental brain disorders are a hallmark of Down syndrome, but what cellular and molecular mechanisms underlie these disorders? This study shows that the excessive number of inhibitory synapses in the neocortex of Down syndrome mouse models is caused by increased levels of Down Syndrome Cell Adhesion Molecule (DSCAM). |
| first_indexed | 2024-04-09T16:06:25Z |
| format | Article |
| id | doaj.art-74b66cc531524704bb62e3a0ac57b5a2 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-04-09T16:06:25Z |
| publishDate | 2023-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-74b66cc531524704bb62e3a0ac57b5a22023-04-25T05:31:19ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852023-04-01214DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse modelsHao LiuRené N. Caballero-FloránTy HergenrederTao YangJacob M. HullGeng PanRuonan LiMacy W. VelingLori L. IsomKenneth Y. KwanZ. Josh HuangPeter G. FuerstPaul M. JenkinsBing YeDown 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. Developmental brain disorders are a hallmark of Down syndrome, but what cellular and molecular mechanisms underlie these disorders? This study shows that the excessive number of inhibitory synapses in the neocortex of Down syndrome mouse models is caused by increased levels of Down Syndrome Cell Adhesion Molecule (DSCAM).https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118173/?tool=EBI |
| spellingShingle | Hao Liu René N. Caballero-Florán Ty Hergenreder Tao Yang Jacob M. Hull Geng Pan Ruonan Li Macy W. Veling Lori L. Isom Kenneth Y. Kwan Z. Josh Huang Peter G. Fuerst Paul M. Jenkins Bing Ye DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models PLoS Biology |
| 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10118173/?tool=EBI |
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