{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE293nnn/GSE293659/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE293659"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Single cell RNA-sequencing reveals neuron type-specific vulnerabilities in a model of STXBP1-related disorder","description":"STXBP1-related disorder (STXBP1-RD) is a severe neurodevelopmental disorder caused by de novo heterozygous mutations that lead to STXBP1 haploinsufficiency. STXBP1-RD is characterised by developmental delay, intellectual disability, early-onset seizures and autistic features. EEG analysis suggests excitation-inhibition (E/I) disbalance. However, STXBP1 is ubiquitously expressed in all neuron types studied so far, and it remains unknown how haploinsufficiency leads to E/I disbalance and STXBP1-RD symptoms. Here, we used single-cell RNA-sequencing to characterize the effect of Stxbp1 haploinsufficiency across all brain cell types in the somatosensory cortex of a validated mouse model. We observed that the relative abundance of cell types was normal. 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.","dates":{"publication":"2026/09/22"},"accession":"GSE293659","cross_references":{"GSM":["GSM8887880"],"GPL":["24247"],"GSE":["293659"],"taxon":["Mus musculus"]}}