Chrna5 genotype determines the long-lasting effects of developmental in vivo nicotine exposure on prefrontal attention circuitry.
Maternal smoking during pregnancy repeatedly exposes the developing fetus to nicotine and is linked with attention deficits in offspring. Corticothalamic neurons within layer VI of the medial prefrontal cortex are potential targets in the disruption of attention circuitry by nicotine, a process termed teratogenesis. These prefrontal layer VI neurons would be likely targets because they are developmentally excited and morphologically sculpted by a population of nicotinic acetylcholine receptors (nAChRs) that are sensitive to activation and/or desensitization by nicotine. The maturational effects of these α4β2* nAChRs and their susceptibility to desensitization are both profoundly altered by the incorporation of an α5 subunit, encoded by the chrna5 gene. Here, we investigate nicotine teratogenesis in layer VI neurons of wildtype and α5(-/-) mice. In vivo chronic nicotine exposure during development significantly modified apical dendrite morphology and nAChR currents, compared with vehicle control. The direction of the changes was dependent on chrna5 genotype. Surprisingly, neurons from wildtype mice treated with in vivo nicotine resembled those from α5(-/-) mice treated with vehicle, maintaining into adulthood a morphological phenotype characteristic of immature mice together with reduced nAChR currents. In α5(-/-) mice, however, developmental in vivo nicotine tended to normalize both adult morphology and nAChR currents. These findings suggest that chrna5 genotype can determine the effect of developmental in vivo nicotine on the prefrontal cortex. In wildtype mice, the lasting alterations to the morphology and nAChR activation of prefrontal layer VI neurons are teratogenic changes consistent with the attention deficits observed following developmental nicotine exposure.
Agency: Canadian Institutes of Health Research, Id: 83422-2
Agency: Canadian Institutes of Health Research, Id: 89825-1
Agency: Canadian Institutes of Health Research, Id: MOP 89825
Prenatal Exposure Delayed Effects
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