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

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Abstract

Introduction

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.

Materials and 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.

Conclusion

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.

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Abbreviations

DA:

dopamine

Ach:

acetylcholine

AchE:

acetylcholinesterase

RL:

reeler homozygous mice

HZ:

reeler heterozygous mice

WT:

wild-type mice

CPF-O:

chlorpyrifos oxon

VEH:

vehicle

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Acknowledgements

This research was supported by the NIH-ISS joint Research Project (0F14) and by Dipartimento Nazionale Anti-Droga, Pres. Cons. Min. (Italy) to GL; by Grants from the National Alliance for Autism Research (NAAR, Princeton, USA) and from the “Associazione Amici del Campus Bio-Medico” (Italy) to FK.

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Authors and Affiliations

  1. Behavioural Neuroscience, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanita’, viale Regina Elena 299, 00161, Rome, Italy

    Giovanni Laviola & Walter Adriani

  2. Laboratory of Developmental Neuroscience, University “Campus Bio-Medico”, Rome, Italy

    Chiara Gaudino, Ramona Marino & Flavio Keller

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  1. Giovanni Laviola
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  2. Walter Adriani
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  3. Chiara Gaudino
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  4. Ramona Marino
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  5. Flavio Keller
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Correspondence to Giovanni Laviola.

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Laviola, G., Adriani, W., Gaudino, C. et al. Paradoxical effects of prenatal acetylcholinesterase blockade on neuro-behavioral development and drug-induced stereotypies in reeler mutant mice. Psychopharmacology 187, 331–344 (2006). https://doi.org/10.1007/s00213-006-0426-z

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