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

ABSTRACT: 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 to changes in the activity of the endocannabinoid anandamide. Here, we have investigated if prenatal VPA induced sex-specific autistic endophenotypes involving anandamide signalling. EXPERIMENTAL APPROACH:We studied sex-specific differences in the ASD-like socio-emotional, cognitive and repetitive symptoms displayed during development of Wistar rats of both sexes, prenatally exposed to VPA. The involvement of anandamide was followed by Western blotting of cannabinoid CB1 receptors and by inhibiting its metabolism. 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, as observed in male rats, prenatal VPA exposure induced selective deficits in social play behaviour and stereotypies in the female rat offspring. At the neurochemical level, prenatal VPA exposure altered phosphorylation of CB1 receptors in a sex-specific, age-specific and tissue-specific manner. Enhancing anandamide signalling through inhibition of its degradation reversed the behavioural deficits displayed by VPA-exposed animals of both sexes. CONCLUSIONS AND IMPLICATIONS:These findings highlight sexually dimorphic consequences of prenatal VPA exposure that may be related to sex-specific effects of VPA on endocannabinoid neurotransmission in the course of development and introduce a new therapeutic target for reversing autistic-like symptoms in both sexes.

SUBMITTER: Melancia F

PROVIDER: S-EPMC6109221 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Melancia Francesca F Schiavi Sara S Servadio Michela M Cartocci Veronica V Campolongo Patrizia P Palmery Maura M Pallottini Valentina V Trezza Viviana V

British journal of pharmacology 20180809 18

<h4>Background and purpose</h4>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 to changes in the activity of the endocannabinoid anandamide. Here, we have investigated if prenatal VPA induced sex-specific autistic endophenotypes involving anandamide sig ...[more]

PMID: 29968249

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Project description:BackgroundAutism spectrum disorder (ASD) is characterized by impaired social interactions and repetitive patterns of behavior. Symptoms appear in early life and persist throughout adulthood. Early social stimulation can help reverse some of the symptoms, but the biological mechanisms of these therapies are unknown. By analyzing the effects of early social stimulation on ASD-related behavior in the mouse, we aimed to identify brain structures that contribute to these behaviors.MethodsWe injected pregnant mice with 600-mg/kg valproic acid (VPA) or saline (SAL) at gestational day 12.5 and evaluated the effect of weaning their offspring in cages containing only VPA animals, only SAL animals, or mixed. We analyzed juvenile play at PD21 and performed a battery of behavioral tests in adulthood. We then used preclinical PET imaging for an unbiased analysis of the whole brain of these mice and studied the function of the piriform cortex by c-Fos immunoreactivity and HPLC.ResultsCompared to control animals, VPA-exposed animals play less as juveniles and exhibit a lower frequency of social interaction in adulthood when reared with other VPA mice. In addition, these animals were less likely to investigate social odors in the habituation/dishabituation olfactory test. However, when VPA animals were weaned with control animals, these behavioral alterations were not observed. Interestingly, repetitive behaviors and depression-related behaviors were not affected by social enrichment. We also found that VPA animals present high levels of glucose metabolism bilaterally in the piriform cortex (Pir), a region known to be involved in social behaviors. Moreover, we found alterations in the somatosensory, motor, and insular cortices. Remarkably, these effects were mostly reversed after social stimulation. To evaluate if changes in glucose metabolism in the Pir correlated with changes in neuronal activity, we measured c-Fos immunoreactivity in the Pir and found it increased in animals prenatally exposed to VPA. We further found increased dopamine turnover in the Pir. Both alterations were largely reversed by social enrichment.ConclusionsWe show that early social enrichment can specifically rescue social deficits in a mouse model of ASD. Our results identified the Pir as a structure affected by VPA-exposure and social enrichment, suggesting that it could be a key component of the social brain circuitry.

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

Publications

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

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