Autism spectrum disorder risk genes have convergent effects on transcription and neuronal firing patterns in primary neurons.

Autism spectrum disorder (ASD) is a highly heterogenous neurodevelopmental disorder with numerous genetic risk factors. Notably, a disproportionate number of risk genes encode transcription regulators including transcription factors and proteins that regulate chromatin. Here, we tested the function of nine such ASD-linked transcription regulators by depleting them in primary cultured neurons. We then defined the resulting gene expression disruptions using RNA-sequencing and tested effects on neuronal firing using multielectrode array recordings. We identified shared gene expression signatures across many ASD risk genes that converged on disruption of critical synaptic genes. Fitting with this, we detected drastic disruptions to neuronal firing throughout neuronal maturation. Together, these findings provide evidence that multiple ASD-linked transcriptional regulators disrupt transcription of synaptic genes and have convergent effects on neuronal firing that may contribute to enhanced ASD risk.