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Mechanisms of Synaptic Zinc Plasticity in Mouse Dorsal Cochlear Nucleus

Vogler, Nathan (2019) Mechanisms of Synaptic Zinc Plasticity in Mouse Dorsal Cochlear Nucleus. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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In many brain areas, such as the neocortex, limbic structures, and the auditory brainstem, glutamatergic nerve terminals also contain zinc in their synaptic vesicles (synaptic zinc). Synaptic zinc is co-released with glutamate to modulate neurotransmission at excitatory synapses, and synaptic zinc modulates sensory processing and behavior. In many zinc-containing brain areas, sensory experience causes long-term changes in synaptic zinc levels and/or signaling, termed here synaptic zinc plasticity. However, the mechanisms underlying synaptic zinc plasticity and the effects of this plasticity on long-term glutamatergic plasticity remain unknown. To study these mechanisms, we employed in vitro and in vivo models in zinc-rich, glutamatergic dorsal cochlear nucleus parallel fiber synapses. Our results demonstrate bidirectional activity-dependent plasticity of synaptic zinc signaling. High-frequency stimulation of parallel fiber synapses induced long-term depression of synaptic zinc signaling (Z-LTD), as evidenced by reduced zinc-mediated inhibition of excitatory postsynaptic currents. Low-frequency stimulation induced long-term potentiation of synaptic zinc signaling (Z-LTP), as evidenced by enhanced zinc-mediated inhibition. Pharmacological inhibition of Group 1 metabotropic glutamate receptors (mGluRs) eliminated both Z-LTD and Z-LTP. Pharmacological activation of Group 1 mGluRs induced bidirectional synaptic zinc plasticity, associated with bidirectional changes in presynaptic zinc levels. Therefore, Group 1 mGluR activation is necessary and sufficient for inducing bidirectional long-term synaptic zinc plasticity. Exposure of mice to loud sound caused Group 1 mGluR-dependent zinc plasticity in parallel fiber synapses, consistent with our in vitro results. To study the downstream mechanisms by which Group 1 mGluRs modulate presynaptic zinc signaling, we further employed our in vitro models in dorsal cochlear nucleus slices, using electrophysiology, pharmacology, and fluorescent imaging. Z-LTD requires a rise in postsynaptic Ca2+. Furthermore, depletion of Ca2+ stores from the endoplasmic reticulum is sufficient to induce Z-LTD, and reduces presynaptic zinc levels. These results demonstrate a role of postsynaptic Ca2+ stores underlying Z-LTD, and suggest a role of retrograde signaling in synaptic zinc plasticity. Together, this work reveals a novel mechanism underlying activity- and experience-dependent plasticity of synaptic zinc signaling, which may be a general plasticity mechanism in zinc-containing synapses throughout the brain.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Vogler, Nathannwv2@pitt.edunwv2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorTzounopoulos,
Committee ChairOswald, Anne-Marie
Committee MemberAizenman, Elias
Committee ChairDong, Yan
Committee MemberMeriney, Stephen
Committee MemberTrussell, Laurence
Date: 19 December 2019
Date Type: Publication
Defense Date: 26 November 2019
Approval Date: 19 December 2019
Submission Date: 5 December 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 135
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: zinc auditory synapses synaptic plasticity
Date Deposited: 19 Dec 2019 20:29
Last Modified: 19 Dec 2021 06:15

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