Autism-associated SCN2A deficiency disrupts cortico-striatal circuitry in human brain assembloids
Xiaoling Chen1,2,3, Jingliang Zhang1,2,3, Jiaxiang Wu1,2
1Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
Biorxiv : the Preprint Server for Biology
|June 12, 2025
Summary
SCN2A mutations disrupt human brain circuits, impairing axonal projections and synaptic transmission, leading to network hyperexcitability. This study reveals human-specific vulnerabilities in SCN2A-related autism spectrum disorder.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Autism spectrum disorder (ASD) is often linked to single-gene mutations.
- SCN2A mutations, specifically protein-truncating variants (PTVs), are highly penetrant in profound ASD.
- Cortico-striatal circuitry is a key node in ASD, but the impact of SCN2A deficiency on human neural circuits remains unclear.
Purpose of the Study:
- To investigate the impact of SCN2A deficiency on human cortico-striatal circuitry.
- To elucidate the mechanisms underlying SCN2A-mediated ASD in human neural models.
Main Methods:
- Utilized a human cortico-striatal assembloid model.
- Analyzed the effects of the SCN2A-C959X mutation on axonal projections, spine density, and synaptic transmission.
- Assessed network excitability in human assembloids.
Main Results:
- SCN2A-C959X PTV impaired long-range cortical axonal projections.
- Reduced striatal spine density and attenuated excitatory cortical-striatal synaptic transmission were observed.
- Heterozygous SCN2A nonsense mutation caused pronounced network hyperexcitability, a human cell-specific phenotype.
Conclusions:
- SCN2A deficiency leads to human circuit-specific dysfunctions.
- The study highlights a human-specific circuit vulnerability in SCN2A-mediated ASD.
- Findings provide insights into the pathophysiology of SCN2A-related neurodevelopmental disorders.
