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Background <p>Schizophrenia, a highly heritable neurodevelopmental disorder characterized by core clinical symptoms such as hallucination, remains poorly understood its polygenic pathogenesis.</p> Methods <p>We selected 11 key schizophrenia risk genes and generated single-gene-knockout-precise-dorsal/ventral-forebrain-organoids via CRISPR-Cas9 system to investigate the polygenic effects of these schizophrenia risk genes on forebrain development via bulk and scRNA-sequencing, multi-electrode array recording and knockout mouse model.</p> Results <p>We found that knockout of 11 risk genes leads to different levels of deficits in human dorsal/ventral forebrain organoids. Notably, <i>CALN1</i> knockout significantly impacted pathways involved in forebrain development and the set of prioritized schizophrenia risk genes. Importantly, <i>Caln1</i>-KO mice exhibited a broad spectrum of schizophrenia-like behaviors, encompassing deficits in spatial memory, social ability and pre-pulse inhibition, alongside spontaneous startle behavior, head-twitch response and hallucination-like perception. At the cellular level, <i>Caln1</i>-deficient mice exhibit abnormal spontaneous abrupt burst spiking in mature layer-5 pyramidal neurons of the prefrontal cortex, and snRNA-seq analysis of <i>Caln1</i><sup><i>−/−</i></sup> mice revealed severe transcriptional and gene network dysregulation in layer-5 excitatory neurons.</p> Conclusions <p>This study reveals that <i>CALN1</i> as a pivotal role in schizophrenia risk genes robustly perturb human forebrain development and cause a broad spectrum of schizophrenia behaviors in mice.</p>

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Convergence of schizophrenia risk genes on CALN1 disrupts human forebrain development and drives core psychotic behaviors including hallucination-like perception

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Hui-Juan Li,
  • Xiao Yu,
  • Xi Liu,
  • Xihua Chen,
  • Jinhong Xu,
  • Jinlong Chen,
  • Tianlin Cheng,
  • Sangmi Chung,
  • Yousheng Shu,
  • Zhicheng Shao

摘要

Background

Schizophrenia, a highly heritable neurodevelopmental disorder characterized by core clinical symptoms such as hallucination, remains poorly understood its polygenic pathogenesis.

Methods

We selected 11 key schizophrenia risk genes and generated single-gene-knockout-precise-dorsal/ventral-forebrain-organoids via CRISPR-Cas9 system to investigate the polygenic effects of these schizophrenia risk genes on forebrain development via bulk and scRNA-sequencing, multi-electrode array recording and knockout mouse model.

Results

We found that knockout of 11 risk genes leads to different levels of deficits in human dorsal/ventral forebrain organoids. Notably, CALN1 knockout significantly impacted pathways involved in forebrain development and the set of prioritized schizophrenia risk genes. Importantly, Caln1-KO mice exhibited a broad spectrum of schizophrenia-like behaviors, encompassing deficits in spatial memory, social ability and pre-pulse inhibition, alongside spontaneous startle behavior, head-twitch response and hallucination-like perception. At the cellular level, Caln1-deficient mice exhibit abnormal spontaneous abrupt burst spiking in mature layer-5 pyramidal neurons of the prefrontal cortex, and snRNA-seq analysis of Caln1−/− mice revealed severe transcriptional and gene network dysregulation in layer-5 excitatory neurons.

Conclusions

This study reveals that CALN1 as a pivotal role in schizophrenia risk genes robustly perturb human forebrain development and cause a broad spectrum of schizophrenia behaviors in mice.