Autism-associated SCN2A deficiency disrupts cortico-striatal circuitry in human brain assembloids.

SCN2A deficiency impairs cortico-striatal circuitry in human brain assembloids, reducing synaptic connectivity despite increased neuronal excitability, with a 50% reduction in cortical projections.

• Why it matters: Understanding how single-gene mutations like SCN2A contribute to ASD is crucial for developing targeted therapies, as the disorder involves disrupted neural circuits, especially cortico-striatal pathways.
• What they did: Using human cortico-striatal assembloids, researchers modeled heterozygous SCN2A truncating variants and observed deficits in cortical projections, striatal spine density, and synaptic transmission, alongside increased neuronal excitability.
• The result: Restoring SCN2A expression via viral gene delivery rescued circuit deficits, highlighting the potential for gene replacement therapies to treat SCN2A-related ASD by correcting circuit dysfunctions.