Paradoxical effects of prenatal acetylcholinesterase blockade on neuro-behavioral development and drug-induced stereotypies in reeler mutant mice.

BACKGROUND

Epidemiological and experimental studies support a link between genetic and epigenetic factors in vulnerability to develop enduring neurobehavioral alterations. We studied the interplay between genetic vulnerability and the prenatal exposure to a neurotoxic compound. Chlorpyrifos, a potent and reversible acetylcholinesterase blocker used as a pesticide, and the "reeler" mouse, lacking the extracellular-matrix protein Reelin, were used.

METHODS

Homozygous reeler (RL), heterozygous (HZ), and wild-type (WT) mice were prenatally exposed to chlorpyrifos-oxon (CPF-O), the active metabolite of chlorpyrifos, or to vehicle (prenatal controls) on gestation days 14-16, that is, during a peak period of neurogenesis in the cerebral cortex. The offspring was reared by the natural dam and tested during infancy and at adulthood for global consequences of the prenatal exposure.

CONCLUSIONS

The results are consistent with complex interactions between genetic (reeler genotype) and epigenetic (prenatal exposure to CPF-O) factors. In the case of some "genetically modulated" parameters (ultrasound vocalization, amphetamine-induced locomotion, and stereotypy), exposure to CPF-O paradoxically reverted the effects produced by progressive reelin absence. Conversely, for an "epigenetically modulated" parameter (grasping reflex maturation), the effects of CPF-O exposure were counteracted by progressive reelin absence. Finally, for parameters apparently untouched by either factor alone (righting reflex latency, scopolamine-induced locomotor activity), prenatal CPF-O exposure unmasked an otherwise latent genotype dependency. This complex picture also points to reciprocal adaptations within cholinergic and dopaminergic systems during development. Data are interesting in view of recently discovered cholinergic abnormalities in autism and schizophrenia, and may suggest new avenues for early intervention.