Risperidone regulates the expression of schizophrenia-related genes in the forebrain of adult male mice.

Introduction: Risperidone is a widely used antipsychotic that reduces psychotic symptoms through modulation of monoaminergic signaling. At the cellular level, however, its effects extend beyond receptor antagonism and induce spatially discrete transcriptional responses across forebrain structures, particularly in the basal ganglia and frontal cortex. Methods: We applied sequencing-based spatial transcriptomics to the forebrain of male C57BL/6N mice following acute risperidone treatment (0.5 mg/kg, i.p.). Unsupervised clustering of spatial transcriptomic profiles accurately delineated cortical divisions, cortical layers, and basal ganglia subregions. Differential expression analysis within anatomically defined clusters, performed using a customized statistical framework, revealed transcriptional patterns that were highly structure-specific and distinct between cortical and basal ganglia regions. Results: Acute risperidone treatment significantly affected 95 transcripts across 12 brain regions. The most prominent transcriptional changes were concentrated in ventral forebrain structures, including the olfactory tubercle (25 differentially expressed transcripts), diagonal band nucleus (22), corpus callosum and commissures (13), and lateral septal nucleus (9). Importantly, 18 of these 95 genes have previously been implicated in schizophrenia, including Discussion: Together, these findings indicate that acute treatment with risperidone in male mice exerts pronounced molecular effects in medial and ventral forebrain regions with high oligodendrocyte and glial cell abundance. Moreover, enrichment analysis points to a molecular convergence between risperidone-induced transcription and genetic pathways implicated in schizophrenia.