title: Prenatal carbon monoxide impairs migration of interneurons into the cerebral cortex.
abstract: Prenatal exposure to carbon monoxide (CO) disrupts brain development, however little is known about effects on neocortical maturation. We exposed pregnant mice to CO from embryonic day 7 (E7) until birth. To study the effect of CO on neuronal migration into the neocortex we injected BrdU during corticogenesis and observed misplaced BrdU+ cells. The majority of cells not in their proper layer colocalized with GAD65/67, suggesting impairment of interneuron migration; interneuron subtypes were also affected. We subsequently followed interneuron migration from E15 organotypic cultures of mouse neocortex exposed to CO; the leading process length of migrating neurons diminished. To examine an underlying mechanism, we assessed the effects of CO on the cellular cascade mediating the cytoskeletal protein vasodilator-stimulated phosphoprotein (VASP). CO exposure resulted in decreased cGMP and in a downstream target, phosphorylated VASP. Organotypic cultures grown in the presence of the phosphodiesterase inhibitor IBMX resulted in a recovery of the leading processes. These data support the idea that CO acts as a signaling molecule and impairs function and neuronal migration by acting through the CO/NO-cGMP pathway. In addition, treated mice demonstrated functional impairment in behavioral tests.
authors.affiliation: Graduate Program in Neuroscience, Uniformed Services University, Bethesda, MD 20814, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Trentini
authors.affiliation: Graduate Program in Neuroscience, Uniformed Services University, Bethesda, MD 20814, USA; Department of Pediatrics, Uniformed Services University, Bethesda, MD 20814, USA.
authors.forename: J Timothy
authors.initials: JT
authors.lastname: O'Neill
authors.affiliation: Graduate Program in Neuroscience, Uniformed Services University, Bethesda, MD 20814, USA; Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD 20814, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Poluch
authors.affiliation: Graduate Program in Neuroscience, Uniformed Services University, Bethesda, MD 20814, USA; Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD 20814, USA. Electronic address: sharon.juliano@usuhs.edu.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Juliano
mesh_terms: D000367:Age Factors; D000818:Animals; D000963:Antimetabolites / Q000633:toxicity*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002248:Carbon Monoxide / Q000633:toxicity*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002540:Cerebral Cortex / Q000196:embryology / Q000254:growth & development / Q000473:pathology*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000378:metabolism; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000473:pathology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000963:Antimetabolites; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D002248:Carbon Monoxide; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2; D001973:Bromodeoxyuridine; D006152:Cyclic GMP
keywords: BrdU; Carbon monoxide; Interneuron; Neocortical development; Neuronal migration