Multiomics analysis identifies VPA-induced changes in neural progenitor cells, ventricular-like regions, and cellular microenvironment in dorsal forebrain organoids.

Schizophrenia is a chronic and highly disabling mental disorder with high heritability [–]. It affects approximately 1% of the population, yet effective long-term treatments are lacking. Despite its substantial heritability, the molecular mechanisms underlying schizophrenia pathophysiology remain poorly understood. Large-scale genome-wide association studies (GWAS) have identified hundreds of genomic loci associated with schizophrenia susceptibility [, ]. More recently, exome sequencing studies have uncovered genes whose rare LoF coding variants significantly increase schizophrenia risk, with effect sizes much larger than those of common GWAS variants []. These high-impact mutations often lead to premature protein truncation, and modeling their LoF may provide insights into the biological mechanisms driving the disease risk. One such gene is , which encodes Exportin-7, a nuclear export receptor with broad substrate specificity []. plays a critical role in nucleocytoplasmic transport, a fundamental process essential for maintaining cellular homeostasis. has been implicated in various biological processes, including erythroid nuclear maturation, tumor suppression, and oncogenesis [–]. While is widely expressed across all regions of the brain, as indicated by Genotype-Tissue Expression (GTEx) data [], its specific neuronal functions remain largely uncharacterized. One report showed that regulates Hedgehog signaling by exporting Gli2 from the nucleus, a pathway essential for neural development and differentiation []. A recent study demonstrated that haploinsufficiency in mice results in cognitive and social behavioral deficits, alongside disruptions in the nuclear transport of molecules associated with schizophrenia genetics []. These findings suggest that XPO7 plays an important role in maintaining normal neuronal function. To investigate the impact of LoF on the neurobiology of human neurons, we utilized human iPSC-derived neurons to model disease risk in vitro [, ]. iPSC-derived neurons have been employed to explore both common and rare genetic risk factors for schizophrenia. Studies using neurons derived from schizophrenia-discordant twins have reported reduced morphological complexity, increased excitability, and decreased synaptic activity, accompanied by dysregulated expression of synapse-related genes [, ]. In another study leveraging a cohort of iPSC-derived neurons from individuals with high schizophrenia polygenic risk scores (PRSs), elevated Na channel activity was observed and found to correlate with clinical symptoms and cognitive performance []. Recent investigations have also examined the effects of rare, high-impact genetic variants. For example, human excitatory neurons with LoF, implicated by schizophrenia genetics, exhibit dysregulated synaptic function and irregular network activity [, ]. Similarly, schizophrenia-associated heterozygous deletions induce synaptic dysfunction and disrupt neuronal network synchrony []. Moreover, LoF of , a Na channel gene associated with both schizophrenia and autism spectrum disorders (ASD), impairs excitatory and inhibitory neurogenesis and leads to abnormal neuronal network activity [, ]. Together, these findings highlight the utility of iPSC-derived neurons for modeling disease-associated phenotypes and potential converging and diverging cellular phenotypes in human neurons associated with schizophrenia risk.