Sex specific autistic endophenotypes induced by prenatal exposure to valproic acid involve anandamide signaling.

BACKGROUND AND PURPOSE:

Autism spectrum disorder (ASD) is more commonly diagnosed in males than in females. Prenatal exposure to the antiepileptic drug valproic acid (VPA) is an environmental risk factor of ASD. Male rats prenatally exposed to VPA show socio-emotional autistic-like dysfunctions that have been related with changes in the activity of the endocannabinoid anandamide. Our aim was to investigate whether prenatal VPA induces sex specific autistic endophenotypes involving anandamide signaling.

EXPERIMENTAL APPROACH:

We studied sex-specific differences in the ASD-like socio-emotional, cognitive and repetitive symptoms displayed in the course of development by rats prenatally exposed to VPA, and investigated the role of anandamide in the autistic-like symptoms displayed by VPA-exposed rats of both sexes.

KEY RESULTS:

Female rats were less vulnerable to the deleterious effects of prenatal VPA exposure on social communication, emotional reactivity and cognitive performance than male rats. Conversely, similarly to what happens in male rats, prenatal VPA exposure induced selective deficits in social play behavior and stereotypies in the female rat offspring. At the neurochemical level, prenatal VPA exposure altered the phosphorylation of CB1 cannabinoid receptors in a sex-, age- and tissue-specific manner. Enhancing anandamide signaling through inhibition of its degradation reversed the behavioral deficits displayed by VPA-exposed animals of both sexes.

CONCLUSION AND IMPLICATION:

These findings highlight sexually-dimorphic consequences of prenatal VPA exposure that may be related to a sex-specific impact of VPA on endocannabinoid neurotransmission in the course of development, and introduce a new therapeutic target for reversing autistic-like symptoms in both sexes.

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