Mobile zinc as a modulator of sensory perception

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TL;DR

This review describes how mobile zinc, released from presynaptic vesicles in glutamatergic neurons, acts as a conserved modulator that attenuates neurotransmission in sensory systems including audition, olfaction, and vision. Using fluorescent sensors (e.g., ZP1, DA-ZP1, LZ9) and fast chelators (e.g., ZX1), the authors demonstrate that zinc binding to postsynaptic NMDA and AMPA receptors downregulates excitatory postsynaptic currents, thereby fine-tuning signal intensity. These findings have clinical implications for understanding sensory processing and for potential therapeutic interventions in conditions such as noise-induced hearing loss, olfactory dysfunction, and ocular injuries.

Full summary

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**Background** Mobile zinc (Zn²⁺) is co-released with glutamate from presynaptic vesicles in certain glutamatergic neurons, where it competes for binding sites on postsynaptic receptors such as NMDA and AMPA receptors. Despite known roles in neurotransmission, the specific function of zinc in sensory perception remained unclear. This review summarizes recent advances using fluorescent sensors and fast chelators to elucidate zinc's role in audition, olfaction, and vision.

**Methods** The authors describe the development and application of small-molecule fluorescent sensors (e.g., Zinpyr-1 [ZP1], diacetyl-ZP1 [DA-ZP1], SpiroZin2, and the ratiometric sensor LZ9) that enable real-time imaging of mobile zinc in live brain slices and in vivo. Key chemical tools include the fast extracellular chelator ZX1 (Kd = 1.0 nM for Zn²⁺, ~200 times faster than calcium-EDTA), the membrane-permeable chelator TPEN (Kd = 0.7 fM), and the less toxic TPA. Experiments were performed in wild-type (WT) and ZnT3 knockout mice, using electrophysiology (EPSC recordings), fluorescence microscopy, and behavioral assays (e.g., odorant exposure).

**Key Results** - **Audition**: In the dorsal cochlear nucleus (DCN), DA-ZP1 staining revealed mobile zinc in the molecular layer but not deep layers. Electrical stimulation released zinc, detected by LZ9, and this release was abolished by 20 µM ZX1. ZnT3 knockout mice showed no zinc accumulation. Electrophysiology showed that ZX1 increased NMDA- and AMPA-receptor-mediated EPSCs in WT but not ZnT3 knockout mice. Noise-exposed mice had reduced vesicular zinc levels, as ZX1 did not affect EPSCs in tissue from noise-exposed animals. - **Olfaction**: ZP1 staining of olfactory bulb slices showed zinc in glomerular (GL) and granule cell (GCL) layers. Electrical stimulation released zinc, and ZX1 increased EPSCs at NMDA receptors. In vivo, odorant-induced synaptic activity was enhanced by ZX1, and direct application of zinc sulfate reduced activity reversibly. ZX1 caused global synaptic firing, indicating zinc normally suppresses background noise. - **Vision**: X-ray fluorescence and immunohistochemistry localized zinc to retinal and choroid tissues, with light/dark adaptation causing zinc migration between nuclear layers. Zinc inhibits NMDA receptor responses in tiger salamander retinal ganglion cells (completely and reversibly) and modulates AMPA and GABA receptors in fish retinas. In optic nerve crush, ZX1 chelation prevented cell death and allowed nerve regeneration. In retinal ischemia, TPEN or calcium-EDTA pretreatment inhibited degeneration. Zinc supplementation (zinc oxide) showed therapeutic benefit for age-related macular degeneration (AMD) in a large prospective study.

**Clinical Implications** Mobile zinc acts as a conserved "brake" that attenuates sensory neurotransmission, protecting circuits from overload and enhancing signal-to-noise ratio. Fast zinc chelation (e.g., ZX1) may be beneficial after ocular injuries (optic nerve crush, retinal ischemia) and could inform treatments for noise-induced hearing loss or olfactory dysfunction. Zinc supplementation may help prevent AMD progression, though plasma zinc levels are not reliable indicators of local zinc concentrations. The development of rapid, selective chelators and ratiometric sensors is critical for future therapeutic and diagnostic applications.