Prenatal cocaine exposure and AMPA receptor signaling in the brain.
Item
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Title
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Prenatal cocaine exposure and AMPA receptor signaling in the brain.
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Identifier
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AAI3295018
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identifier
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3295018
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Creator
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Bakshi, Kalindi Parikh.
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Contributor
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Adviser: Hoau-Yan Wang
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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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Prenatal cocaine exposure compromises glutamatergic alpha-amino 3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPAR)-regulated synaptic transmission, whereas the molecular mechanism underlying AMPAR deficits is unclear. Using brain tissues from 21-day-old in utero cocaine-exposed rats, we tested the hypothesis that deficient AMPA transmission in the prenatal cocaine-exposed brain is caused by a reduced synaptic membrane recruitment of AMPARs. Our results show that synaptic membrane expression of AMPAR subunits-GluR1, GluR2 and GluR3 is markedly reduced in the frontal cortex of cocaine-exposed rats. Further, the attenuated synaptic membrane targeting of GluR2/3 in prenatal-cocaine exposed progeny is a result of reduced interaction between GluR2/3 and glutamate receptor interacting protein (GRIP1/2), a PDZ domain protein that mediates the synaptic delivery of GluR2/3. The reduced GRIP--AMPAR interaction is caused by persistent GRIP phosphorylation by protein kinase C (PKC)- and Src tyrosine kinase. To further understand the molecular mechanisms involved in these changes, the role of GRIP-associated protein, GRASP-1, a neuronal rasGEF that interacts with both GRIP and AMPARs in inhibiting synaptic targeting of AMPARs was examined. Our results show an overall increase in the cytosolic and synaptic membrane levels of GRASP-1 along with an increase in GRIP1/2 and GRASP-1 coupling in the frontal cortex of the prenatal cocaine-exposed brain. We found a reduced GRASP-1 RasGEF activity in the prenatal cocaine-exposed brain followed by an increase in the levels of active/GTP bound small G proteins, RhoA, Rac1/Cdc42 and Rap1 which belong to the Ras superfamily. Moreover, we detected high levels of F-actin in prenatal cocaine exposed progeny which maybe indicative of changes in AMPAR trafficking. These results suggest that change in the phosphorylation state of GRIP not only reduces the synaptic targeting of GluR2/3 but also affects AMPAR trafficking in the prenatal cocaine-exposed brain.
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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.
