# Synaptic and intrinsic membrane defects disrupt early neural network dynamics in Down syndrome

## TL;DR

This study shows that Down syndrome disrupts early brain cell activity through faulty connections and ion channels, leading to cognitive issues.

## Contribution

The study identifies specific synaptic and ion channel defects in Down syndrome neurons using isogenic human-derived models.

## Key findings

- Trisomy 21 causes impaired glutamatergic synaptic connectivity and altered K+ and Na+ channel activity.
- A-type K+ channels, specifically Kv4.3, are critical in Down syndrome neurodevelopmental defects.
- These defects disrupt neural network activity and neuron synchrony during development.

## Abstract

Down syndrome, caused by trisomy 21, affects around six million people worldwide and features learning, memory and language deficits. However, the mechanisms underlying trisomy 21 neurophenotypes involving human cortical circuitry are unknown. By characterising developing neural network dynamics and single cell excitability profiles, from synaptic and voltage-dependent ion channel behaviour using an isogenic induced pluripotent stem cell-derived neuronal model, we show that trisomy 21 impairs the activity and development of cortical circuitry. This is caused by deficient glutamatergic synaptic connectivity and by aberrant intrinsic membrane properties involving K+ and Na+ channels culminating in spike firing defects that weaken neural network activity and disrupt the synchrony of developing neurons. We also identify transiently activated A-type K+ channels, specifically Kv4.3 channels, as a key orchestrator for Down syndrome during neurodevelopment. Overall, these excitability changes will significantly contribute towards the aberrant neurophenotypes observed later on in life.

Down syndrome (DS) increases gene dosage that disrupts neurodevelopment and cognition. Using human-derived isogenic neurons, this study reveals altered network activity, synaptic dysfunction, and ion channel defects underlying DS neural impairment.