Disrupted mossy fiber connections from defective embryonic neurogenesis contribute to SOX11-associated schizophrenia

Abnormal mossy fiber connections in the hippocampus have been implicated in schizophrenia. However, it remains unclear whether this abnormality in the patients is genetically determined and whether it contributes to the onset of schizophrenia. Here, we showed that iPSC-derived hippocampal NPCs from schizophrenia patients with the A/A allele at SNP rs16864067 exhibited abnormal NPC polarity, resulting from the downregulation of SOX11 by this high-risk allele. In the SOX11-deficient mouse brain, abnormal NPC polarity was also observed in the hippocampal dentate gyrus, and this abnormal NPC polarity led to defective hippocampal neurogenesis-specifically, irregular neuroblast distribution and disrupted granule cell morphology. As granule cell synapses, the mossy fiber pathway was disrupted, and this disruption was resistant to activity-induced mossy fiber remodeling in SOX11 mutant mice. Moreover, these mutant mice exhibited diminished PPI and schizophrenia-like behaviors. Activation of hippocampal neurogenesis in the embryonic brain, but not in the adult brain, partially alleviated disrupted mossy fiber connections and improved schizophrenia-related behaviors in mutant mice. We conclude that disrupted mossy fiber connections are genetically determined and strongly correlated with schizophrenia-like behaviors in SOX11-deficient mice. This disruption may reflect the pathological substrate of SOX11-associated schizophrenia.

Automated summary

Abnormal mossy fiber connections in the hippocampus have been found in patients with schizophrenia, but the genetic basis and its contribution to the development of schizophrenia were unclear. This study demonstrated that a high-risk allele of SNP rs16864067 downregulated the SOX11 gene, leading to abnormal polarity in hippocampal neural progenitor cells derived from schizophrenia patients. A mouse model with SOX11 deficiency showed similar abnormal polarity and hippocampal neurogenesis defects, resulting in disrupted mossy fiber connections and schizophrenia-like behaviors. Activation of hippocampal neurogenesis during embryonic development partially alleviated these disruptions and improved schizophrenia-related behaviors.