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<p>Understanding the complex interplay between gene expression and neuronal activity is crucial for unraveling the molecular mechanisms underlying cognitive function and neurological disorders. Here, we developed pooled screens using CRISPR interference (CRISPRi) and the fluorescent calcium integrator CaMPARI2 to evaluate genetic modifiers of neuronal depolarization. Using this screening method, we evaluated 1343 genes for their effect on depolarization in a human iPSC-derived neuron model, revealing potential links to neurodegenerative and neurodevelopmental disorders. These genes include known regulators of neuronal excitability, such as TARPs and ion channels, as well as genes associated with autism spectrum disorder and Alzheimer’s disease not previously described to affect neuronal depolarization. This CRISPRi-based screening platform offers a versatile tool to uncover molecular mechanisms controlling neuronal function in health and disease.</p>

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A massively parallel CRISPR-based screening platform for modifiers of neuronal depolarization

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月1日

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  • Steven C. Boggess,
  • Vaidehi Gandhi,
  • Ming-Chi Tsai,
  • Emily Marzette,
  • Noam Teyssier,
  • Joanna Yu-Ying Chou,
  • Xiaoyu Hu,
  • Amber Cramer,
  • Lin Yadanar,
  • Kunal Shroff,
  • Claire G. Jeong,
  • Celine Eidenschenk,
  • Jesse E. Hanson,
  • Ruilin Tian,
  • Martin Kampmann

摘要

Understanding the complex interplay between gene expression and neuronal activity is crucial for unraveling the molecular mechanisms underlying cognitive function and neurological disorders. Here, we developed pooled screens using CRISPR interference (CRISPRi) and the fluorescent calcium integrator CaMPARI2 to evaluate genetic modifiers of neuronal depolarization. Using this screening method, we evaluated 1343 genes for their effect on depolarization in a human iPSC-derived neuron model, revealing potential links to neurodegenerative and neurodevelopmental disorders. These genes include known regulators of neuronal excitability, such as TARPs and ion channels, as well as genes associated with autism spectrum disorder and Alzheimer’s disease not previously described to affect neuronal depolarization. This CRISPRi-based screening platform offers a versatile tool to uncover molecular mechanisms controlling neuronal function in health and disease.