Department of Science, Section of Biomedical Sciences and Technologies, University 'Roma Tre', Rome, Italy.
Department of Physiology and Pharmacology 'V. Erspamer', Sapienza University of Rome, Rome, Italy.
Br J Pharmacol. 2018 Sep;175(18):3699-3712. doi: 10.1111/bph.14435. Epub 2018 Aug 9.
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.
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 CB receptors and by inhibiting its metabolism.
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 CB 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.
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.
自闭症谱系障碍（ASD）在男性中的诊断率高于女性。产前暴露于抗癫痫药物丙戊酸（VPA）是 ASD 的环境危险因素。产前暴露于 VPA 的雄性大鼠表现出社会情感自闭症样功能障碍，这与内源性大麻素大麻素的活性变化有关。在这里，我们研究了是否存在涉及大麻素信号的产前 VPA 诱导的性别特异性自闭症表型。
我们研究了 Wistar 大鼠在发育过程中表现出的 ASD 样社会情感、认知和重复症状的性别特异性差异，这些大鼠均为产前暴露于 VPA。通过 Western blot 分析大麻素 CB 受体的表达和抑制其代谢来研究大麻素的参与情况。
与雄性大鼠相比，雌性大鼠对产前 VPA 暴露对社会交流、情绪反应和认知表现的不良影响的易感性较低。相反，正如在雄性大鼠中观察到的那样，产前 VPA 暴露诱导雌性大鼠后代选择性地缺乏社交游戏行为和刻板行为。在神经化学水平上，产前 VPA 暴露以性别特异性、年龄特异性和组织特异性的方式改变 CB 受体的磷酸化。通过抑制其降解来增强内源性大麻素信号可逆转 VPA 暴露动物的行为缺陷。
这些发现强调了产前 VPA 暴露的性别二态性后果，这可能与 VPA 在发育过程中对内源性大麻素神经传递的性别特异性影响有关，并为逆转两性自闭症样症状引入了一个新的治疗靶点。
