In:
PLOS Biology, Public Library of Science (PLoS), Vol. 21, No. 4 ( 2023-4-20), p. e3002078-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3002078
DOI:
10.1371/journal.pbio.3002078.g001
DOI:
10.1371/journal.pbio.3002078.g002
DOI:
10.1371/journal.pbio.3002078.g003
DOI:
10.1371/journal.pbio.3002078.g004
DOI:
10.1371/journal.pbio.3002078.g005
DOI:
10.1371/journal.pbio.3002078.g006
DOI:
10.1371/journal.pbio.3002078.s001
DOI:
10.1371/journal.pbio.3002078.s002
DOI:
10.1371/journal.pbio.3002078.s003
DOI:
10.1371/journal.pbio.3002078.s004
DOI:
10.1371/journal.pbio.3002078.s005
DOI:
10.1371/journal.pbio.3002078.s006
DOI:
10.1371/journal.pbio.3002078.s007
DOI:
10.1371/journal.pbio.3002078.s008
DOI:
10.1371/journal.pbio.3002078.s009
DOI:
10.1371/journal.pbio.3002078.s010
DOI:
10.1371/journal.pbio.3002078.s011
DOI:
10.1371/journal.pbio.3002078.s012
DOI:
10.1371/journal.pbio.3002078.s013
DOI:
10.1371/journal.pbio.3002078.s014
DOI:
10.1371/journal.pbio.3002078.s015
DOI:
10.1371/journal.pbio.3002078.r001
DOI:
10.1371/journal.pbio.3002078.r002
DOI:
10.1371/journal.pbio.3002078.r003
DOI:
10.1371/journal.pbio.3002078.r004
DOI:
10.1371/journal.pbio.3002078.r005
DOI:
10.1371/journal.pbio.3002078.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2126773-X
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