Altered neuronal network activity and connectivity in human Down Syndrome excitatory cortical neurons DOI Creative Commons
Manuel Peter, Raquel Real, Alessio Strano

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

Abstract Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting one in 600 live births worldwide, and caused by trisomy human chromosome 21 (Hsa21). Here, we investigated whether results changes excitatory neuron network development, that could contribute to neurodevelopmental phenotypes DS. Replaying cerebral cortex development vitro with Trisomy control isogenic non-isogenic induced pluripotent stem cells (hiPSC) enabled analysis effect Hsa21 triplication on neural activity connectivity specifically developing cortical neurons. Network revealed a significant decrease neuronal TS21 neurons early development. showed marked reduction synchronised bursting up 80 days over 5 months vivo following transplantation into mouse forebrain. Viral transynaptic tracing identified networks , suggesting reduced contributes absence bursting. Expression voltage-gated potassium channels was significantly neurons, single recordings confirmed lack hyperpolarization-activated currents, indicating functional loss potassium/sodium cyclic nucleotide-gated channel 1 (HCN1) DS We conclude leads ion composition, networks, all which collectively are likely some features

Language: Английский

Single-nucleus analysis reveals dysregulated oxidative phosphorylation in Down syndrome basal forebrain at birth DOI Creative Commons
Nicole West, Kalpana Hanthanan Arachchilage, Sara Knaack

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Abstract INTRODUCTION Basal forebrain cholinergic neurons (BFCNs) are integral to learning, attention, and memory, prone degeneration in Down syndrome (DS), Alzheimer’s disease, other neurodegenerative diseases. However, the mechanisms that lead of these not known. METHODS Single-nuclei gene expression ATAC sequencing were performed on postmortem human basal from unaffected control DS tissue samples at 0-2 years age (n=4 each). RESULTS Sequencing analysis identifies differences early postnatal life. Genes encoding proteins associated with energy metabolism pathways, specifically oxidative phosphorylation glycolysis, genes antioxidant enzymes upregulated BFCNs. DISCUSSION Multiomic analyses reveal may be disrupted BFCNs by birth. Increased accumulation reactive oxygen species byproducts contributors BFCN neurodegeneration.

Language: Английский

Citations

0
Altered neuronal network activity and connectivity in human Down Syndrome excitatory cortical neurons DOI Creative Commons
Manuel Peter, Raquel Real, Alessio Strano

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 28, 2024

Abstract Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting one in 600 live births worldwide, and caused by trisomy human chromosome 21 (Hsa21). Here, we investigated whether results changes excitatory neuron network development, that could contribute to neurodevelopmental phenotypes DS. Replaying cerebral cortex development vitro with Trisomy control isogenic non-isogenic induced pluripotent stem cells (hiPSC) enabled analysis effect Hsa21 triplication on neural activity connectivity specifically developing cortical neurons. Network revealed a significant decrease neuronal TS21 neurons early development. showed marked reduction synchronised bursting up 80 days over 5 months vivo following transplantation into mouse forebrain. Viral transynaptic tracing identified networks , suggesting reduced contributes absence bursting. Expression voltage-gated potassium channels was significantly neurons, single recordings confirmed lack hyperpolarization-activated currents, indicating functional loss potassium/sodium cyclic nucleotide-gated channel 1 (HCN1) DS We conclude leads ion composition, networks, all which collectively are likely some features

Language: Английский

Citations

0