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

Scientists studied autism-linked genes in lab-grown brain cells. They found that when these genes don't work properly, they disrupt other genes needed for brain cells to connect and communicate. This caused problems with how brain cells send electrical signals. The research suggests different autism genes may cause similar problems in brain cell function, helping explain how genetic changes might lead to autism.

This laboratory study examined nine autism-linked genes that regulate gene expression by testing their effects in cultured brain cells. Researchers removed these genes from neurons and measured changes in gene activity and electrical firing patterns. The study found that different autism risk genes caused similar disruptions to genes important for brain cell connections (synapses). These genetic changes also altered how neurons fire electrical signals throughout their development.

The findings suggest that multiple autism-related genes may contribute to autism risk through shared pathways affecting synaptic function and neuronal communication, providing insight into potential biological mechanisms underlying autism spectrum disorder.

Results suggest that targeting synaptic gene expression or neuronal firing patterns could be therapeutic approaches for autism. The convergent effects across multiple risk genes indicate that different genetic causes of autism may benefit from similar interventions focused on synaptic function and neuronal communication.

Study conducted only in cultured neurons, not whole brain tissue or living organisms. Sample size and specific statistical methods not reported. Findings may not fully reflect complex in vivo neuronal interactions and developmental processes.

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.