Prenatal carbon monoxide impairs migration of interneurons into the cerebral cortex

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.