# Cell-specific Synaptic Plasticity in the Auditory Brainstem

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $573,627

## Abstract

Project Summary
As an essential element for cellular function, divalent zinc is a cofactor in a large number enzymes and
regulatory proteins. Since the surprising discovery that zinc is concentrated within synaptic vesicles in many
excitatory synapses in the brain, including in more than 50% of excitatory presynaptic terminals in neocortical
areas, numerous investigators have studied the possible roles of this metal during neurotransmission.
Nonetheless, due to the paucity of zinc–selective tools optimized for neurobiological studies, the physiological
roles of zinc during synaptic transmission remained elusive until recently. Our recent studies, funded by this
grant, used novel tools for chelating and tracking zinc in central synapses and established zinc as an inhibitory
neuromodulator in excitatory synapses. In response to a single presynaptic action potential, synaptic zinc is
released and inhibits postsynaptic glutamate AMPA receptors (AMPARs). Moreover, during repetitive synaptic
stimulation, zinc inhibits extrasynaptic glutamate NMDA receptors (NMDARs) and is necessary along with
GPR39, a putative metabotropic zinc-sensing receptor, for activation of endocannabinoid signaling and
glutamate release inhibition. These effects are experience-dependent because loud sound reduced
presynaptic zinc levels and abolished zinc inhibition of AMPARs, implicating zinc in experience-dependent
AMPAR synaptic plasticity. The establishment of a novel endogenous neuromodulator, acting in many
excitatory synapses throughout the brain, reveals the significance of the work and poses three questions of
fundamental importance to excitatory synaptic signaling and auditory processing: a) what are the dynamics of
the different forms of zinc-mediated inhibition and how do they interact among themselves and with glutamate
neurotransmission to shape excitatory glutamatergic signaling, b) what are the molecular mechanisms
underlying long-lasting, activity-dependent changes in presynaptic zinc levels and how do they interact with
other established plasticity mechanisms, and c) what are the characteristics of auditory stimuli that trigger zinc
release in vivo and how does zinc release affect spontaneous and sound-evoked activity in awake animals.
Answering these questions will contribute significantly not only to the fields of zinc biology and hearing
research, but will also reveal general mechanisms that will be of great interest to the wider neuroscience
community. In Aims 1 and 2, we will employ in vitro brain slice experiments and use auditory brainstem
synapses as models for studying the role of zinc in neurotransmission and plasticity. In Aim 3, we will employ
in vivo imaging to investigate the role of these mechanisms in auditory cortical processing in unanesthetized
mice.

## Key facts

- **NIH application ID:** 9857585
- **Project number:** 5R01DC007905-15
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Thanos Tzounopoulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $573,627
- **Award type:** 5
- **Project period:** 2007-02-08 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857585

## Citation

> US National Institutes of Health, RePORTER application 9857585, Cell-specific Synaptic Plasticity in the Auditory Brainstem (5R01DC007905-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857585. Licensed CC0.

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