Lactate-Mediated Brain Acidosis Drives Epigenetic Dysregulation of TGFB2 and Associated Gene Networks in Schizophrenia and Bipolar Disorder

Gene expression analyses of postmortem brains have identified hundreds of dysregulated genes in schizophrenia (SCZ) and bipolar disorder (BD). Lactate accumulation and reduced brain pH are also consistently reported in these disorders. As increased TGFB expression has been implicated in major psychiatric diseases and lactic acid induces TGFB2 upregulation in metabolic diseases, we hypothesized that lactate-induced brain acidosis may drive widespread gene dysregulation through TGFB2 activation. In our previous microarray studies, increased TGFB2 expression was observed in postmortem brains of SCZ and BD patients, while pathway analyses suggested a key role for TGFB2 in the dysregulation of other genes, particularly astrocytic genes. TGFB2 itself also exhibited promoter DNA hypomethylation in postmortem brains of these patients. Here, while brain pH was lower in SCZ and BD patients, we investigated the effects of pH alteration on the expression and promoter DNA methylation of TGFB2 and TGFB2-correlated genes in iPSC-derived neurons, astrocytes, and brain organoids (brainoids). Cultures were treated with lactic acid, HCl, bicarbonate, or NaOH to alter culture medium pH by ±0.4 units, and gene expression and promoter DNA methylation were evaluated by qPCR analyses. In our reanalysis of postmortem brain microarray data, nearly 80% of dysregulated genes, together with TGFB2, exhibited inverse correlations with brain pH. Lactic acid treatment induced increased expression and promoter DNA hypomethylation of TGFB2 and several correlated genes in astrocytes and brainoids, whereas bicarbonate and NaOH treatments showed opposite effects. These findings suggest that lactate-mediated brain acidosis may contribute to TGFB2 upregulation and widespread gene dysregulation implicated in SCZ and BD pathogenesis. Therapeutic interventions targeting lactic acid accumulation or TGFB2 hyperexpression may mitigate disease-associated brain gene dysregulation.