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

Alekh Paranjapye; Rili Ahmad; Steven Su; Abraham J. Waldman; Jennifer E. Phillips-Cremins; Shuo Zhang; Erica Korb

doi:10.1101/gr.280698.125

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

¹Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
²Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
³Department of Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

↵4 These authors contributed equally to this work.

Corresponding author: ekorb{at}pennmedicine.upenn.edu

Abstract

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 test the function of nine such ASD-linked transcription regulators by depleting them in primary cultured neurons. We then define the resulting gene expression disruptions using RNA sequencing and test effects on neuronal firing using multielectrode array recordings. We identify shared gene expression signatures across many ASD-risk genes that converge on the disruption of critical synaptic genes. Fitting with this, we detect robust disruptions to neuronal firing throughout neuronal maturation. Together, these findings provide evidence that the loss of multiple ASD-linked transcriptional regulators disrupts transcription of synaptic genes and has convergent effects on neuronal firing that may contribute to enhanced ASD risk.

Footnotes

[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.280698.125.

Received March 25, 2025.
Accepted September 25, 2025.

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