Dysregulation of miRNAs Drives Premature GABAergic Maturation and Early Neurodevelopmental Defects in Schizophrenia

ABSTRACT Background Schizophrenia (SCZ) is a severe neurodevelopmental disorder with numerous genetic risk loci. However, little is known about the molecular alterations that occur during brain development in SCZ, particularly regarding the role of microRNA (miRNA) mediated regulatory mechanisms. This gap in knowledge is largely due to the limited availability of developing human brain tissue. Patient-derived brain organoids offer a promising alternative model. Here we use 3D dorsal forebrain organoids (DFOs) to investigate miRNA dysregulation in SCZ. Methods DFOs were generated from human induced pluripotent stem cells (hiPSCs) derived from six SCZ patients and five matched controls and cultured for 120 days. Multi-omics analyses, immunohistochemistry, and in situ hybridization were employed to characterize molecular and spatial features. Results DFOs recapitulated key molecular hallmarks of human cortical development. Nineteen miRNAs were differentially expressed in SCZ: nine associated with neural progenitor proliferation were downregulated and ten linked to neuronal differentiation and synaptic maturation were upregulated, reflecting a compressed developmental timeline. Among 77 dysregulated mRNAs, 55 were predicted miRNA targets. SCZ DFOs exhibited significant upregulation of GABAergic pathway genes accompanied by altered expression of their regulatory miRNAs, indicating premature GABAergic lineage specification. The disrupted miRNA–mRNA network converged on glutamatergic and dopaminergic development, synaptic organization, and extracellular matrix remodeling. Conclusion Dysregulated miRNAs in SCZ DFOs disrupt neuronal differentiation, excitatory–inhibitory balance, and early circuit formation, implicating miRNA-mediated post-transcriptional regulation as a key mechanism linking molecular alterations to cellular and network-level deficits in SCZ.