title: Prenatal Cocaine Exposure Alters BDNF-TrkB Signaling in the Embryonic and Adult Brain.
abstract: Prenatal cocaine exposure remains a major public health concern because of its adverse effects on cognitive function. Although the molecular mechanisms underlying the cognitive impairment are not fully understood, brain-derived neurotrophic factor (BDNF) signaling via its receptor tyrosine kinase B (TrkB) is emerging as a potential candidate. We used a mouse model to examine the impact of ongoing cocaine exposure on BDNF expression in the dorsal forebrain on embryonic day 15 (E15) as well as the long-term effects of prenatal cocaine exposure on BDNF-TrkB signaling in the frontal cortex in early postnatal (postnatal day 16; P16) and adult (P60) male and female mice. We found that ongoing cocaine exposure decreased BDNF expression in the E15 dorsal forebrain, prenatal cocaine exposure did not alter BDNF or TrkB (total or phosphorylated) expression in the frontal cortex at P16, and that the prenatal cocaine exposure produced significant increases in BDNF, the activated (phosphorylated) form of TrkB, as well as Bdnf mRNA in the frontal cortex at P60. The increase in BDNF protein and mRNA expression at P60 was concurrent with hyperacetylation of histone H3 at the Bdnf promoter in the frontal cortex. The increase in frontal cortical BDNF and activated TrkB at P60 occurred in male but not female mice. Thus, our data demonstrate that ongoing cocaine exposure produces a decrease in BDNF expression in the embryonic brain, and that prenatal cocaine exposure produces a sex-specific increase in frontal cortical BDNF-TrkB signaling at P60 only in male mice. Lastly, hyperacetylation of histone H3 at the Bdnf promoter is one epigenetic mechanism mediating the effects of prenatal cocaine exposure on Bdnf expression at P60 in male mice.
authors.affiliation: Center for Brain Repair, Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA.
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: McCarthy
authors.forename: Kaly A
authors.initials: KA
authors.lastname: Mueller
authors.forename: Elisa N
authors.initials: EN
authors.lastname: Cannon
authors.forename: Megan N
authors.initials: MN
authors.lastname: Huizenga
authors.forename: Shayna B
authors.initials: SB
authors.lastname: Darnell
authors.forename: Pradeep G
authors.initials: PG
authors.lastname: Bhide
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000254:growth & development; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D005260:Female; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D016548:Prosencephalon / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D003042:Cocaine