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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\n                    <jats:italic>Drosophila<\/jats:italic>\n                    homolog of DSCAM determines the size of presynaptic terminals. However, whether the triplication of\n                    <jats:italic>DSCAM<\/jats:italic>\n                    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\n                    <jats:italic>DSCAM<\/jats:italic>\n                    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\n                    <jats:italic>DSCAM<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3002078","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T13:21:18Z","timestamp":1681996878000},"page":"e3002078","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":31,"title":["DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models"],"prefix":"10.1371","volume":"21","author":[{"given":"Hao","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 N.","family":"Caballero-Flor\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ty","family":"Hergenreder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob M.","family":"Hull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geng","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruonan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Macy W.","family":"Veling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori L.","family":"Isom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth Y.","family":"Kwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. 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