Analysis of neuronal activity impairment in iPSC-derived neurons from idiopathic autism patients

Understanding the molecular mechanisms underlying autism spectrum disorder (ASD) is crucial to develop effective interventions. Here, we utilized induced pluripotent stem cells differentiated into neurons (iPSC-Ns) from idiopathic ASD and control individuals (CTRL) to investigate the molecular basis of ASD. ASD-iPSC-Ns exhibited functional alterations displaying less calcium transients compared to CTRL. Different expression levels of microRNAs involved in neurogenesis and neuronal functioning might underlie these differences. ASD-iPSC-N neuronal networks showed impaired synaptic neurotransmission and connectivity (decreased [Ca²⁺]_i waves and glutamatergic transmission), as demonstrated by a chemogenetic approach utilizing designer receptor exclusively activated by designer drug (DREADD) in co-cultures of iPSC-Ns and rat cortical neurons. Such functional alterations have profound implications for neuronal network formation and function, contributing to the core pathogenic features of ASD. Therefore, utilization of ASD-iPSC-Ns offers a unique opportunity to study the molecular mechanism in a relevant human cellular context. Our findings highlight the significance of neuronal activity and synaptic dysfunction in ASD pathogenesis.