title: Cocaine alters BDNF expression and neuronal migration in the embryonic mouse forebrain.
abstract: Prenatal cocaine exposure impairs brain development and produces lasting alterations in cognitive function. In a prenatal cocaine exposure mouse model, we found that tangential migration of GABA neurons from the basal to the dorsal forebrain and radial neuron migration within the dorsal forebrain were significantly decreased during the embryonic period. The decrease in the tangential migration occurred early in gestation and normalized by late gestation, despite ongoing cocaine exposure. The decrease in radial migration was associated with altered laminar positioning of neurons in the medial prefrontal cortex. The cocaine exposure led to transient decreases in the expression of Tbr2 and Tbr1, transcription factors associated with intermediate progenitor cells and newborn neurons of the dorsal forebrain, respectively, although neurogenesis was not significantly altered. Since cocaine can modulate brain derived neurotrophic factor (BDNF) expression in the mature brain, we examined whether cocaine can alter BDNF expression in the embryonic brain. We found a transient decrease in BDNF protein expression in the cocaine-exposed embryonic forebrain early in gestation. By late gestation, the BDNF expression recovered to control levels, despite ongoing cocaine exposure. In basal forebrain explants from cocaine-exposed embryos, cell migration was significantly decreased, corroborating the in vivo data on tangential GABA neuron migration. Since BDNF can influence tangential neuronal migration, we added BDNF to the culture medium and observed increased cell migration. Our data suggest that cocaine can alter tangential and radial neuronal migration as well as BDNF expression in the embryonic brain and that decreased BDNF may mediate cocaine's effects on neuronal migration.
authors.affiliation: Department of Neurology and NeuroEpigenetcis Laboratory, MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: McCarthy
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Shayna B
authors.initials: SB
authors.lastname: Darnell
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Sangrey
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Sadri-Vakili
authors.forename: Pradeep G
authors.initials: PG
authors.lastname: Bhide
mesh_terms: D000367:Age Factors; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004622:Embryo, Mammalian; D005260:Female; D055879:Gene Knock-In Techniques / Q000379:methods; D005968:Glutamate Decarboxylase / Q000235:genetics; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000096:biosynthesis; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000503:physiopathology; D016548:Prosencephalon / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000502:physiology; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000096:biosynthesis; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; C491198:Eomes protein, mouse; D009687:Nuclear Proteins; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D003042:Cocaine