Single cell RNA-sequencing reveals neuron type-specific vulnerabilities in a model of STXBP1-related disorder

The most prominent transcriptomic changes occurred in GABAergic and glutamatergic neurons, especially Sncg interneurons and deep-layer pyramidal neurons. Astrocytes exhibited substantial changes despite not expressing STXBP1, suggesting a non-cell autonomous response. Differentially expressed genes showed little overlap between neuronal types but accumulated in synaptic and translation-related GO terms.

This was accompanied by a strong trend towards reduced protein translation as measured by puromycin incorporation. Excitatory neurons showed greater synaptic dysregulation than inhibitory neurons. Notably, neuronal transcriptome changes greatly overlapped with prior proteomics STXBP1-RD data but differed radically from other disorders.

Seizure burden correlated positively in astrocytes and negatively in neurons to expression of translation-related genes. These findings identify cell-type specific vulnerabilities to STXBP1 haploinsufficiency which may explain hyperexcitability, network dysfunction and cognition deficits in STXBP1-RD. Overall, our study provides a cellular-resolution map of the transcriptomic changes in STXBP1-related disorders, providing potential new therapeutic targets.