Activity-dependent phosphorylation of dynamin 1 at serine-857 in mouse hippocampus---Implications for learning and memory.
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Title
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Activity-dependent phosphorylation of dynamin 1 at serine-857 in mouse hippocampus---Implications for learning and memory.
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Identifier
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AAI3284412
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identifier
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3284412
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Creator
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Xie, Wen.
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Contributor
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Adviser: Andrzej Wieraszko
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Date
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2007
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience
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Abstract
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Dynamin 1 (Dyn1) is a brain-enriched large GTPase which participates in endocytosis, a process required for synaptic vesicle recycling and receptor internalization. Dyn1 is a phospho-protein whose level of phosphorylation is dependent on cell membrane potentials. Thus, the function of Dyn1 phosphorylation in synaptic transmission has been proposed and studied. Dyn1 is primarily phosphorylated at Serine-857 (S857) by minibrain/dual specificity tyrosine phosphorylation regulated kinase 1A (Mnb/Dyrk1A), which is linked to mental retardation of Down syndrome (DS). Phosphorylation at S857 regulates the interactions of Dyn1 with many endocytic accessory proteins in vitro. I chose the system of neuronal transmission in the Schaffer collateral/commissural - CA1 pathway from mouse hippocampus to investigate the regulation of Dyn1 phosphorylation at S857 in vivo. I found that the phosphorylation/dephosphorylation of Dyn1 was a dynamic physiological event that correlated with neuronal activity. Dyn1 was highly phosphorylated in nonstimulated slices, while the level of phosphorylation changed in response to different types of electrical stimulation. The dephosphorylation was Ca2+/calcineurin dependent and was mediated by AMPA/kainate receptors. An immunohistochemical study revealed that the distribution pattern of phosphorylated Dyn1 was also dependent on neuronal activity. In addition, as the primary kinase phosphorylating Dyn1 at S857, Mnb/Dyrk1A was also activated by neuronal activity. Together, these studies demonstrate that the phosphorylation of Dyn1 at S857 by Mnb/Dyrk1A is dynamically regulated by synaptic connections in mouse hippocampus.;To explore the involvement of Mnb/Dyrk1A in the learning and memory deficits of DS, a potential Mnb/Dyrk1A inhibitor, (-)-Epigallocatechin-3-Gallate (EGCG), was evaluated for its ability to alter neuronal plasticity in mouse hippocampus. EGCG had a promoting effect on LTP induction in wild-type mouse. Most strikingly, EGCG restored the impaired LTP induction in Ts65Dn mouse, the most studied mouse model for DS. Ts65Dn mouse over-expresses a group of genes that are syntenic to those in human chromosome 21 including the gene of Mnb/Dyrk1A. Although the mechanism(s) underlying the effect are still missing, the study not only implicates Mnb/Dyrk1A in DS, but also demonstrates a possible pharmacological intervention for DS.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
