Altered Expression of GABA-Related Genes in Schizophrenia: Insights from Meta-Analyses of Brain and Blood Samples and iPSC-Derived Organoids

Schizophrenia, one of the most disabling mental disorders, affects approximately seven per 1000 individuals worldwide and has an estimated heritability of around 80%; however, its pathophysiology remains incompletely understood. The disorder has been linked to dysregulation of multiple neurotransmitter systems, including dopamine, serotonin, γ-aminobutyric acid (GABA), and glutamate. GABA, the primary inhibitory neurotransmitter in the central nervous system, is synthesized by the enzymes glutamic acid decarboxylase 67 (GAD67) and glutamic acid decarboxylase 65 (GAD65), encoded by the GAD1 and GAD2 genes, respectively. The genes (SST) and parvalbumin (PVALB) encode somatostatin and parvalbumin, which are characteristic markers of specialized GABAergic interneuron subpopulations involved in maintaining excitatory-inhibitory balance and supporting cortical circuit function. While reduced GAD1 expression has been consistently reported in schizophrenia, findings regarding GAD2 expression have been inconsistent.

In this study, we examined the expression of GAD1, GAD2, SST, and PVALB across three biological levels: postmortem brain tissue, peripheral blood samples, and patient-derived induced pluripotent stem cell (iPSC)-derived brain organoids, compared with healthy controls. The meta-analysis of brain tissue included seven independent datasets (295 samples: 151 individuals with schizophrenia and 144 healthy controls) and was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Patient-derived iPSC organoids were used to investigate early neurodevelopmental alterations, while a separate meta-analysis of peripheral blood gene expression included 293 samples (160 schizophrenia, 133 controls) to explore biomarker potential.

Both GAD1 and GAD2 were significantly downregulated in postmortem brain samples (meta-analytic effect sizes <-0.5) and in iPSC-derived organoids, supporting the hypothesis that reduced expression of these genes emerges prior to clinical onset and may contribute to disease development. In contrast, decreased expression of SST and PVALB was observed in brain tissue but not in organoids, suggesting that alterations in these interneuron markers may occur at later stages of the disease. Notably, reduced PVALB expression was also detected in peripheral blood samples, indicating its potential utility as a peripheral biomarker for schizophrenia.

Further studies are required to clarify the causal role of reduced GABAergic activity in schizophrenia pathogenesis and to evaluate the clinical relevance of PVALB expression for diagnosis and treatment monitoring.