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 (April 2023) DSCAM gene triplication causes excessive GABAergic synapses in the neocortex in Down syndrome mouse models. PLoS Biology, 21 (4). e3002078. ISSN 1544-9173

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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.

Item Type:	Paper
Subjects:	diseases & disorders diseases & disorders > mental disorders > genetic disorders > Down syndrome organism description > animal > insect > Drosophila diseases & disorders > mental disorders organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > mental disorders > genetic disorders organism description > animal > insect organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > tissues types and functions > neocortex organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions organs, tissues, organelles, cell types and functions > sub-cellular tissues: types and functions > synapse
CSHL Authors:	Huang, Z. Josh
Communities:	CSHL labs > Huang lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	April 2023
Date Deposited:	22 Sep 2023 14:37
Last Modified:	10 Jan 2024 20:20
PMCID:	PMC10118173
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/40970

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