Prenatal carbon monoxide impairs migration of interneurons into the cerebral cortex

John F Trentini; J Timothy O'Neill; Sylvie Poluch; Sharon L Juliano

doi:10.1016/j.neuro.2015.11.002

Prenatal carbon monoxide impairs migration of interneurons into the cerebral cortex

Neurotoxicology. 2016 Mar:53:31-44. doi: 10.1016/j.neuro.2015.11.002. Epub 2015 Nov 12.

Authors

John F Trentini¹, J Timothy O'Neill², Sylvie Poluch³, Sharon L Juliano⁴

Affiliations

¹ Graduate Program in Neuroscience, Uniformed Services University, Bethesda, MD 20814, USA.
² Graduate Program in Neuroscience, Uniformed Services University, Bethesda, MD 20814, USA; Department of Pediatrics, Uniformed Services University, Bethesda, MD 20814, USA.
³ Graduate Program in Neuroscience, Uniformed Services University, Bethesda, MD 20814, USA; Department of Anatomy, Physiology and Genetics, Uniformed Services University, Bethesda, MD 20814, USA.
⁴ 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.

PMID: 26582457
DOI: 10.1016/j.neuro.2015.11.002

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.

Keywords: BrdU; Carbon monoxide; Interneuron; Neocortical development; Neuronal migration.

Published by Elsevier B.V.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Age Factors
Animals
Antimetabolites / toxicity*
Bromodeoxyuridine / metabolism
Carbon Monoxide / toxicity*
Cell Adhesion Molecules / metabolism
Cell Movement / drug effects*
Cerebral Cortex / embryology
Cerebral Cortex / growth & development
Cerebral Cortex / pathology*
Cyclic GMP / metabolism
Dose-Response Relationship, Drug
Female
Gene Expression Regulation, Developmental / drug effects
Glutamate Decarboxylase / metabolism
In Vitro Techniques
Interneurons / drug effects*
Locomotion / drug effects
Locomotion / physiology
Mice
Microfilament Proteins / metabolism
Microtubule-Associated Proteins / metabolism
Phosphoproteins / metabolism
Pregnancy
Prenatal Exposure Delayed Effects / chemically induced*
Prenatal Exposure Delayed Effects / pathology

Substances

Antimetabolites
Cell Adhesion Molecules
Microfilament Proteins
Microtubule-Associated Proteins
Mtap2 protein, mouse
Phosphoproteins
vasodilator-stimulated phosphoprotein
Carbon Monoxide
Glutamate Decarboxylase
glutamate decarboxylase 1
glutamate decarboxylase 2
Bromodeoxyuridine
Cyclic GMP

Abstract

Publication types

MeSH terms

Substances

Grants and funding