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UTILIZING PRESYNAPTIC STRUCTURE-FUNCTION PROPERTIES TO INFORM THE DESIGN OF NOVEL THERAPIES FOR NEUROMUSCULAR DISEASE

Tarr, Tyler B. (2016) UTILIZING PRESYNAPTIC STRUCTURE-FUNCTION PROPERTIES TO INFORM THE DESIGN OF NOVEL THERAPIES FOR NEUROMUSCULAR DISEASE. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The mammalian neuromuscular junction (NMJ) is consistently reliable, but disorders with a synaptic locus can adversely affect this reliability and lead to muscle weakness. One such disorder is Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder that causes a reduction in neurotransmitter release at the NMJ by reducing the number of release-relevant presynaptic calcium channels. In addition to removing calcium channels, it is hypothesized that LEMS causes a disruption in the organization of release sites, or active zones. Therefore, understanding how active zone structure and organization regulate functional properties in both normal and diseased NMJs would be beneficial for the targeting of treatment for synaptic pathologies. Here we show evidence suggesting that the mammalian NMJ is built with hundreds to thousands of unreliable single-vesicle release sites, and this organization leads to both overall reliability during single action potentials and a conservation of resources such that reliability is maintained during periods of high-frequency activity. We then show that this unreliability at a single-vesicle level likely has two low probability components, the low probability of a calcium channel opening near a vesicle and the low probability that a vesicle will be released even when a nearby channel does open. Furthermore, the low probability of these two components becomes pathologically low in LEMS, and targeting both components simultaneously with a potassium channel blocker and a novel calcium channel agonist leads to a supra-linear increase in transmitter release at LEMS model synapses. Although this dual treatment completely restores the magnitude of transmitter release, the short-term plasticity characteristics are not restored to normal levels. Using an MCell model of the mouse NMJ active zone, we show that simply reducing the number of channels does not recapitulate the short-term facilitation observed experimentally in LEMS model mouse NMJs. Instead, it seems that a combination of a reduction in the number of channels tightly coupled to the vesicle and an increase in the number of channels that are loosely coupled to vesicles is more representative of LEMS short-term plasticity characteristics. This information could help determine novel treatment approaches for LEMS and other synaptic disorders.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tarr, Tyler B.tbt2@pitt.eduTBT2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMeriney, Stephen D.meriney@pitt.eduMERINEY
Committee MemberThiels, Eddathiels@pitt.eduTHIELS
Committee MemberJohnson, Jon W.jjohnson@pitt.eduJJOHNSON
Committee MemberBarrionuevo, Germangerman@pitt.eduGERMAN
Committee MemberOswald, Anne-Marie Mamoswald@pitt.eduAMOSWALD
Committee MemberGrinnell, Alan D.adg@mednet.ucla.edu
Committee MemberDittrich, Markusdittrich@psc.edu
Date: 22 January 2016
Date Type: Publication
Defense Date: 10 August 2015
Approval Date: 22 January 2016
Submission Date: 16 September 2015
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 189
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Neuroscience
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: presynaptic neurotransmitter release calcium channels neuromuscular
Date Deposited: 22 Jan 2016 17:16
Last Modified: 15 Nov 2016 14:30
URI: http://d-scholarship.pitt.edu/id/eprint/26129

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