Imaging and recording of synaptic zinc in the brain by covalent chemistry-based semisynthetic biosensors.

Authors

Hao Zhu, Seiji Sakamotob, Keisuke Nakamura, Chengli Qiu, Kohei Nakajima, Hiroshi Nonaka, Itaru Hamachi

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 42. Pages e2606947123. Oct 20, 2026. Epub Oct 12, 2026.

Abstract

Labile zinc ions (Zn²⁺) are stored in glutamatergic vesicles at specific excitatory synapses in the central nervous system and released into synaptic clefts in an activity-dependent manner. However, the precise roles of synaptic Zn²⁺ remain unclear due to a lack of tools capable of analyzing Zn²⁺ with synapse-level spatial resolution in vivo. Here, we developed neuroreceptor-based semisynthetic biosensors that function as integrating dosimeters, recording synaptic Zn²⁺ by covalent chemistry in the living mouse brain. Using a chemical knock-in strategy, we introduced activity-based Zn²⁺ probes with distinct affinities into endogenous α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid or γ-aminobutyric acid type A receptors. These in-brain-constructed Zn²⁺ sensors enabled region-specific mapping of Zn²⁺ in synaptic clefts in the living mouse brain. Imaging-based analyses revealed differences in apparent Zn²⁺ levels at excitatory and inhibitory synapses across hippocampal regions during kainate-induced seizures, providing insights into the physiological and pathological functions of synaptic Zn²⁺.

PMID:
42863051
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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