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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 (Unpublished)

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Abstract

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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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Vogler, Nathannwv2@pitt.edunwv2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorTzounopoulos, Thanosthanos@pitt.edu
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 2019 20:29
URI: http://d-scholarship.pitt.edu/id/eprint/38058

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