Cell-type-specific transcriptional responses to clozapine and risperidone in mouse frontal cortex

Treatment-resistant schizophrenia (TRS) represents a major clinical challenge, with clozapine being the only antipsychotic with proven efficacy. To investigate the cellular mechanisms underlying clozapine’s unique therapeutic profile, we analyzed transcriptional responses to clozapine and risperidone across major brain cell types. Microglia, astrocytes and neurons were acutely enriched from mouse frontal cortex using an immunopanning approach following 14 days of antipsychotic treatment. Bulk RNA sequencing was performed on each enriched cell population, and cell-type-specific transcriptional programs were characterized using differential expression analysis, gene set enrichment analysis and functional network integration. Deconvolution approaches were applied to validate cell-type enrichment. This dataset enables the exploration of shared and drug-specific molecular pathways across brain cell types and provides a resource to study cellular mechanisms relevant to treatment-resistant schizophrenia.