title: Prenatal Cocaine Exposure Upregulates BDNF-TrkB Signaling.
abstract: Prenatal cocaine exposure causes profound changes in neurobehavior as well as synaptic function and structure with compromised glutamatergic transmission. Since synaptic health and glutamatergic activity are tightly regulated by brain-derived neurotrophic factor (BDNF) signaling through its cognate tyrosine receptor kinase B (TrkB), we hypothesized that prenatal cocaine exposure alters BDNF-TrkB signaling during brain development. Here we show prenatal cocaine exposure enhances BDNF-TrkB signaling in hippocampus and prefrontal cortex (PFCX) of 21-day-old rats without affecting the expression levels of TrkB, P75NTR, signaling molecules, NMDA receptor-NR1 subunit as well as proBDNF and BDNF. Prenatal cocaine exposure reduces activity-dependent proBDNF and BDNF release and elevates BDNF affinity for TrkB leading to increased tyrosine-phosphorylated TrkB, heightened Phospholipase C-γ1 and N-Shc/Shc recruitment and higher downstream PI3K and ERK activation in response to ex vivo BDNF. The augmented BDNF-TrkB signaling is accompanied by increases in association between activated TrkB and NMDARs. These data suggest that cocaine exposure during gestation upregulates BDNF-TrkB signaling and its interaction with NMDARs by increasing BDNF affinity, perhaps in an attempt to restore the diminished excitatory neurotransmission.
authors: Departments of Physiology, Pharmacology and Neuroscience, School of Medicine at CCNY, The City University of New York, New York, New York, 10031, United States of America.|Department of Biology, Neuroscience Program, Graduate School of The City University of New York, New York, New York, 10061, United States of America.
authors: Andres
authors: A
authors: Stucky
authors: Departments of Physiology, Pharmacology and Neuroscience, School of Medicine at CCNY, The City University of New York, New York, New York, 10031, United States of America.
authors: Kalindi P
authors: KP
authors: Bakshi
authors: Departments of Physiology, Pharmacology and Neuroscience, School of Medicine at CCNY, The City University of New York, New York, New York, 10031, United States of America.
authors: Eitan
authors: E
authors: Friedman
authors: Departments of Physiology, Pharmacology and Neuroscience, School of Medicine at CCNY, The City University of New York, New York, New York, 10031, United States of America.
authors: Hoau-Yan
authors: HY
authors: Wang
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000779:Anesthetics, Local; D019208:Brain-Derived Neurotrophic Factor; D019869:Phosphatidylinositol 3-Kinases; D020813:Receptor, trkB; D003042:Cocaine