Prenatal cocaine dysregulates BDNF--TrkB and p75(NTR) signaling in the hippocampus and prefrontal cortex of adolescent
Item
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Title
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Prenatal cocaine dysregulates BDNF--TrkB and p75(NTR) signaling in the hippocampus and prefrontal cortex of adolescent
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Identifier
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d_2009_2013:52b01acb600c:11746
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identifier
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12362
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Creator
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Stucky, Andres Wood,
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Contributor
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Hoau-Yan Wang
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Date
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2013
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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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Neurosciences | Pharmacology | BDNF | Cocaine | NMDA | TrkB
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Abstract
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Brain-derived neurotrophic factor (BDNF) upregulates glutamatergic transmission and N-Methyl-D-Aspartate receptor (NMDAR) function through the activation of tropomyosin-related kinase receptor type B (TrkB). Conversely, NMDAR activation influences BDNF release. Because prenatal cocaine exposure can markedly alter glutamatergic transmission and NMDAR activation, we hypothesized that a dysregulation of the glutamatergic system following prenatal cocaine exposure could result in long-lasting alteration of TrkB signaling, thereby influencing the interaction between TrkB and glutamatergic NMDARs. In agreement with this hypothesis, we found that activated (i.e. tyrosine-phosphorylated) TrkB (pY-TrkB) levels in response to exogenous BDNF were increased in both the prefrontal cortex and hippocampus of 21-day-old rats that were exposed prenatally to cocaine. This cocaine-induced effect was corroborated by an elevated pY-TrkB-associated phospholipase, C-gamma1, and adapter protein, Shc, as well as increases in downstream extracellular signal-regulated kinase 2 (ERK2) and PI3K signaling.;We report a significant decrease in the levels of BDNF released at the synapse of prenatal cocaine- exposed rats compared to control after NMDA and K+ stimulation and a marked increased affinity of receptor TrkB to its ligand BDNF. This suggests that increased activation and signaling of TrkB in prenatal cocaine- exposed rats is the result of increased affinity of TrkB to BDNF, possibly as a functional compensation for decreased levels of activity-dependent BDNF released at the synapse. Moreover, we found a decreased activity of the p75 neurotrophin receptor(p75NTR) death-inducing pathways, as assessed by p75NTR recruitment of adaptor proteins TRADD, FADD, and TRAF2/6, and corroborated by decreased downstream Janus kinase 1 (JNK1) activation, as indicated by lower JNK1 phosphorylation (p-JNK1) levels.;Our data suggest that BDNF--TrkB and BDNF--/proBDNF-p75 NTR activities are reduced following prenatal cocaine exposure due to a marked reduction in BDNF/Thrown Away proBDNF release. Given that neurotrophins and glutamate receptors interact to modulate the health and excitability of glutamatergic synapses, upregulation of BDNF--TrkB signaling and downregulation of BDNF--/proBDNF p75NTR pathways suggests a more efficient neurotrophin signaling in an attempt to reestablish synaptic homeostasis when supplies of BDNF are restored.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
