Schiavi Sara, La Rosa Piergiorgio, Petrillo Sara, Carbone Emilia, D'Amico Jessica, Piemonte Fiorella, Trezza Viviana
Department of Science, University "Roma Tre", Rome, Italy.
Division of Neuroscience, Department of Psychology, Sapienza University, Rome, Italy.
Front Psychiatry. 2022 Feb 25;13:851679. doi: 10.3389/fpsyt.2022.851679. eCollection 2022.
Prenatal exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD) in humans and it induces autistic-like behaviors in rodents. Imbalances between GABAergic and glutamatergic neurotransmission and increased oxidative stress together with altered glutathione (GSH) metabolism have been hypothesized to play a role in both VPA-induced embriotoxicity and in human ASD. N-acetylcysteine (NAC) is an antioxidant precursor of glutathione and a modulator of glutamatergic neurotransmission that has been tested in ASD, although the clinical studies currently available provided controversial results. Here, we explored the effects of repeated NAC (150 mg/kg) administration on core autistic-like features and altered brain GSH metabolism in the VPA (500 mg/kg) rat model of ASD. Furthermore, we measured the mRNA expression of genes encoding for scaffolding and transcription regulation proteins, as well as the subunits of NMDA and AMPA receptors and metabotropic glutamate receptors mGLUR1 and mGLUR5 in brain areas that are relevant to ASD. NAC administration ameliorated the social deficit displayed by VPA-exposed rats in the three-chamber test, but not their stereotypic behavior in the hole board test. Furthermore, NAC normalized the altered GSH levels displayed by these animals in the hippocampus and nucleus accumbens, and it partially rescued the altered expression of post-synaptic terminal network genes found in VPA-exposed rats, such as , and in nucleus accumbens, and , and in cerebellum. These data indicate that NAC treatment selectively mitigates the social dysfunction displayed by VPA-exposed rats normalizing GSH imbalance and reestablishing the expression of genes related to synaptic function in a brain region-specific manner. Taken together, these data contribute to clarify the behavioral impact of NAC in ASD and the molecular mechanisms that underlie its effects.
产前暴露于丙戊酸（VPA）是人类自闭症谱系障碍（ASD）的一个风险因素，并且它会在啮齿动物中诱发类似自闭症的行为。γ-氨基丁酸能（GABAergic）和谷氨酸能神经传递之间的失衡、氧化应激增加以及谷胱甘肽（GSH）代谢改变，被认为在VPA诱导的胚胎毒性和人类ASD中都起作用。N-乙酰半胱氨酸（NAC）是谷胱甘肽的抗氧化前体和谷氨酸能神经传递的调节剂，已在ASD中进行了测试，尽管目前可用的临床研究提供了有争议的结果。在这里，我们探讨了重复给予NAC（150毫克/千克）对ASD的VPA（500毫克/千克）大鼠模型中核心自闭症样特征和脑GSH代谢改变的影响。此外，我们测量了与ASD相关的脑区中编码支架和转录调节蛋白的基因，以及NMDA和AMPA受体亚基和代谢型谷氨酸受体mGLUR1和mGLUR5的mRNA表达。给予NAC改善了VPA暴露大鼠在三室试验中表现出的社交缺陷，但没有改善它们在洞板试验中的刻板行为。此外，NAC使这些动物在海马体和伏隔核中显示的改变的GSH水平正常化，并且它部分挽救了在VPA暴露大鼠中发现的突触后终末网络基因的改变表达，例如伏隔核中的 、 和 ，以及小脑中的 、 和 。这些数据表明，NAC治疗以脑区特异性方式选择性减轻VPA暴露大鼠表现出的社交功能障碍，使GSH失衡正常化并重新建立与突触功能相关基因的表达。综上所述，这些数据有助于阐明NAC在ASD中的行为影响及其作用的分子机制。
