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The role of cypin in regulating synaptic content and transmission
Descriptive
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Title
The role of cypin in regulating synaptic content and transmission
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Rodriguez
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Ana R.
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1986-
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Ana R. Rodriguez
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author
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Firestein
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Bonnie L
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Bonnie L Firestein
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chair
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Kenneth
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Kenneth Paradiso
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Zhiping P
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Yarmush
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Martin l
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Martin l Yarmush
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Advisory Committee
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internal member
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Meaney
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David F
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David F Meaney
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outside member
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Madura
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Kiran
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Kiran Madura
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Advisory Committee
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Rutgers University
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degree grantor
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Graduate School - New Brunswick
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theses
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2016
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2016-10
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2016
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xx
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eng
Abstract
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Proper synaptic transmission is essential for normal brain function and requires the precise spatial and functional assembly of molecular signal transduction machinery at synaptic sites and the correct morphology of dendrites and their branches. Defects in synaptogenesis and dendritogenesis are implicated in neurological and neurodevelopmental disorders. Cypin (cytosolic PSD-95 interactor) is a core regulator of dendrite branching and decreases the synaptic clustering of the scaffolding protein PSD-95 in rat hippocampal neurons. This dissertation will explore the functional implications of altering cypin levels on PSD-95 protein and synaptic function. We show that overexpression of cypin decreases synaptic PSD-95 protein levels, increases total PSD-95 protein levels, and increases the frequency of miniature excitatory postsynaptic currents (mEPSCs). We used microelectrode arrays to assess neuronal network dynamics after overexpression of cypin and uncovered changes in spiking variability that were not evident from the study of global network activity. The spike count variability of networks that overexpress cypin increases over time, and this variability is dependent on baseline activity levels. Moreover, attenuation of AMPAR-mediated synaptic transmission with the AMPAR antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) shows that cypin overexpression results in a decrease in functional AMPARs, potentially interfering with synaptic upscaling. Interestingly, we found that the alterations in synaptic transmission with overexpression of cypin are independent of cypin binding to PSD-95, whereas cypin-mediated changes in PSD-95 expression depend on cypin binding to PSD-95. Finally, we show that cypin interacts with the β7 subunit of the proteasome and interferes with its chymotryptic-like activity. Cypin overexpression results in increased ubiquitination of PSD-95, consistent with the observed increase in total PSD-95 levels. Taken together, our results suggest a proteasome-mediated role for cypin in the redistribution of PSD-95, and potentially, remodeling of the postsynaptic density associated with synaptic plasticity.
Subject
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Topic
Biomedical Engineering
Subject
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Topic
Synapses
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Rutgers University Electronic Theses and Dissertations
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ETD_7657
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electronic resource
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1 online resource (viii, 131 p. : ill.)
Note
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Ph.D.
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Includes bibliographical references
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by Ana R. Rodriguez
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Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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doi:10.7282/T3RB76XM
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ETD doctoral
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Rights
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The author owns the copyright to this work.
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Name
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Rodriguez
GivenName
Ana
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R.
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Permission or license
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2016-09-27 21:20:35
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Name
Ana Rodriguez
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Affiliation
Rutgers University. Graduate School - New Brunswick
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Author Agreement License
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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2016-10-31
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2018-10-31
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Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2018.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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