Idiopathic Autism: Cellular and Molecular Phenotypes in Pluripotent Stem Cell-Derived Neurons

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Autism spectrum disorder (ASD) pathophysiology is poorly understood due to limited access to patient neurons.
• Studying rare single-gene syndromes has advanced ASD understanding but represents a small fraction of cases.
• Induced pluripotent stem cells (iPSCs) offer a potential method to study patient-specific neurons.

Purpose of the Study:

• To define cellular and molecular phenotypes in neurons derived from iPSCs of individuals with non-syndromic autism spectrum disorder.
• To investigate differences in neuronal function and gene expression between autistic patients and their unaffected siblings.

Main Methods:

• Generated patient-specific iPSCs from three males with idiopathic autism spectrum disorder and their unaffected siblings.
• Differentiated iPSCs into electrophysiologically active neurons.
• Performed whole-genome microarray analysis to identify differentially expressed genes.

Main Results:

• iPSC-derived neurons from autistic patients exhibited reduced frequency and kinetics of spontaneous excitatory postsynaptic currents.
• Significant decreases in voltage-gated Na+ and inactivating K+ currents were observed in autistic neurons.
• Microarray analysis identified 161 unique differentially expressed genes, enriched for synaptic transmission and previously linked to ASD.

Conclusions:

• iPSC-derived neurons from individuals with idiopathic autism display aberrant voltage-gated currents.
• Underlying molecular changes related to synaptic function are evident in these neurons.
• This study provides a cellular and molecular framework for understanding idiopathic autism spectrum disorder.