Cortical GABAergic neuron dysregulation in schizophrenia is age dependent

Abstract

Cortical GABAergic neuron dysregulation is implicated in schizophrenia (SCZ), but it remains unclear if these changes are due to altered cell proportions or per-cell mRNA changes. We analyzed bulk and cell type-specific RNAseq data from 1,302 individuals to assess SCZ- and age-associated changes in GABAergic interneurons across two neocortical regions. We found that younger SCZ cases (age < 70) showed reduced parvalbumin (PVALB) and somatostatin (SST) cell proportions, while older SCZ cases showed increased proportions compared to controls. Earlier onset SCZ, associated with more severe clinical symptoms, was linked to greater reductions in these cell types. Additionally, there was cohort-specific evidence for reduced per-cell PVALB and SST mRNA in SCZ. Our findings underscore the importance of age-stratified analyses in SCZ, suggesting that distinct pathological processes underlie GABAergic neuron dysregulation across different age- and symptom-severity groups and warranting tailored therapeutic approaches.