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1. Rodriguez, Ana R., 1986-. The role of cypin in regulating synaptic content and transmission.
Degree: PhD, Biomedical Engineering, 2016, Rutgers University
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.Advisors/Committee Members: Firestein, Bonnie L (chair), Paradiso, Kenneth (internal member), Pang, Zhiping P (internal member), Yarmush, Martin l (internal member), Meaney, David F (outside member), Madura, Kiran (outside member).
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APA (6th Edition):
Rodriguez, Ana R., 1. (2016). The role of cypin in regulating synaptic content and transmission. (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/51451/
Chicago Manual of Style (16th Edition):
Rodriguez, Ana R., 1986-. “The role of cypin in regulating synaptic content and transmission.” 2016. Doctoral Dissertation, Rutgers University. Accessed July 11, 2020. https://rucore.libraries.rutgers.edu/rutgers-lib/51451/.
MLA Handbook (7th Edition):
Rodriguez, Ana R., 1986-. “The role of cypin in regulating synaptic content and transmission.” 2016. Web. 11 Jul 2020.
Rodriguez, Ana R. 1. The role of cypin in regulating synaptic content and transmission. [Internet] [Doctoral dissertation]. Rutgers University; 2016. [cited 2020 Jul 11]. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/51451/.
Council of Science Editors:
Rodriguez, Ana R. 1. The role of cypin in regulating synaptic content and transmission. [Doctoral Dissertation]. Rutgers University; 2016. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/51451/