Genetic risk factors acting during pregnancy or early after birth have been proposed to account for the exponential increase of autism diagnoses in the past 20 years. In particular, a potential link with exposure to environmental mercury has been suggested. Male sex constitutes a second risk factor for autism. A third potential genetic risk factor is decreased Reelin expression. Male heterozygous reeler (rl(+/-)) mice show an autism-like phenotype, including Purkinje cells (PCs) loss and behavioral rigidity. We evaluated the complex interactions between 3 risk factors, i.e. genetic status, sex, and exposure to methylmercury (MeHg), in rl(+/-) mice. Mice were exposed to MeHg during the prenatal and early postnatal period, either at a subtoxic dose (2 ppm in Dams' drinking water), or at a toxic dose (6 ppm Dams' drinking water), based on observations in other rodent species and mice strains. We show that: (a) 2 ppm MeHg does not cause PCs loss in the different animal groups, and does not enhance PCs loss in rl(+/-) males; consistent with a lack of overt neurotoxicity, 2 ppm MeHg per se does not cause behavioral alterations (separation-induced ultrasonic calls in newborns, or sociability and social preference in adults); (b) in stark contrast, 6 ppm MeHg causes a dramatic reduction of PCs number in all groups, irrespective of genotype and sex. Cytochrome C release from mitochondria of PCs is enhanced in 6 ppm MeHg-exposed groups, with a concomitant increase of μ-calpain active subunit. At the behavioral level, 6 ppm MeHg exposure strongly increases ultrasonic vocalizations in all animal groups. Notably, 6 ppm MeHg significantly decreases sociability in rl(+/-) male mice, while the 2 ppm group does not show such as decrease. At a subtoxic dose, MeHg does not enhance the autism-like phenotype of male rl(+/-) mice. At the higher MeHg dose, the scenario is more complex, with some "autism-like" features (loss of sociability, preference for sameness) being evidently affected only in rl(+/-) males, while other neuropathological and behavioral parameters being altered in all groups, independently from genotype and sex. Mitochondrial abnormalities appear to play a crucial role in the observed effects.
- Social novelty
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