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<p>Understanding how neurons integrate signals from thousands of input synapses requires methods to monitor neurotransmission across many sites simultaneously. The fluorescent protein glutamate indicator iGluSnFR enables visualization of synaptic signaling, but the sensitivity, scale and speed of such measurements are limited by existing variants. Here we developed two highly sensitive fourth-generation iGluSnFR variants with fast activation and tailored deactivation rates: iGluSnFR4f for tracking rapid dynamics, and iGluSnFR4s for recording from large populations of synapses. These indicators detect glutamate with high spatial specificity and single-vesicle sensitivity in vivo. We used them to record natural patterns of synaptic transmission across multiple experimental contexts in mice, including two-photon imaging in cortical layers 1–4 and hippocampal CA1, and photometry in the midbrain. The iGluSnFR4 variants extend the speed, sensitivity and scalability of glutamate imaging, enabling direct observation of information flow through neural networks in the intact brain.</p>

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Glutamate indicators with increased sensitivity and tailored deactivation rates

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月23日

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  • Abhi Aggarwal,
  • Adrian Negrean,
  • Yang Chen,
  • Rishyashring Iyer,
  • Daniel Reep,
  • Anyi Liu,
  • Anirudh Palutla,
  • Michael E. Xie,
  • Bryan J. MacLennan,
  • Kenta M. Hagihara,
  • Lucas W. Kinsey,
  • Julianna L. Sun,
  • Pantong Yao,
  • Jihong Zheng,
  • Arthur Tsang,
  • Getahun Tsegaye,
  • Yonghai Zhang,
  • Ronak H. Patel,
  • Benjamin J. Arthur,
  • Julien Hiblot,
  • Philipp Leippe,
  • Miroslaw Tarnawski,
  • Jonathan S. Marvin,
  • Jason D. Vevea,
  • Srinivas C. Turaga,
  • Alison G. Tebo,
  • Matteo Carandini,
  • L. Federico Rossi,
  • David Kleinfeld,
  • Arthur Konnerth,
  • Karel Svoboda,
  • Glenn C. Turner,
  • Jeremy P. Hasseman,
  • Kaspar Podgorski

摘要

Understanding how neurons integrate signals from thousands of input synapses requires methods to monitor neurotransmission across many sites simultaneously. The fluorescent protein glutamate indicator iGluSnFR enables visualization of synaptic signaling, but the sensitivity, scale and speed of such measurements are limited by existing variants. Here we developed two highly sensitive fourth-generation iGluSnFR variants with fast activation and tailored deactivation rates: iGluSnFR4f for tracking rapid dynamics, and iGluSnFR4s for recording from large populations of synapses. These indicators detect glutamate with high spatial specificity and single-vesicle sensitivity in vivo. We used them to record natural patterns of synaptic transmission across multiple experimental contexts in mice, including two-photon imaging in cortical layers 1–4 and hippocampal CA1, and photometry in the midbrain. The iGluSnFR4 variants extend the speed, sensitivity and scalability of glutamate imaging, enabling direct observation of information flow through neural networks in the intact brain.