Kazlauskas Nadia, Campolongo Marcos, Lucchina Luciana, Zappala Cecilia, Depino Amaicha Mara
Institute for Physiology, Molecular Biology and Neurosciences, CONICET-UBA, and Department of Physiology, Molecular and Cellular Biology, FCEyN, University of Buenos Aires, C1428EHA, Buenos Aires, Argentina.
Institute for Physiology, Molecular Biology and Neurosciences, CONICET-UBA, and Department of Physiology, Molecular and Cellular Biology, FCEyN, University of Buenos Aires, C1428EHA, Buenos Aires, Argentina.
Psychoneuroendocrinology. 2016 Oct;72:11-21. doi: 10.1016/j.psyneuen.2016.06.001. Epub 2016 Jun 7.
In Autism Spectrum Disorders (ASD), a bias to a higher incidence in boys than in girls has been reported. With the aim to identify biological mechanisms acting in female animals that could underlie this bias, we used an extensively validated mouse model of ASD: the prenatal exposure to valproic acid (VPA). We found postnatal behavioral alterations in female VPA pups: a longer latency in righting reflex at postnatal day (P) 3, and a delay in the acquisition of the acoustic startle response. We also analyzed the density of glial cells in the prefrontal cortex, hippocampus and cerebellum, in VPA and control animals. Female VPA pups showed alterations in the density of astrocytes and microglial cells between P21 and P42, with specific dynamics in each brain region. We also found a decrease in histone 3 acetylation in the cerebellum of female VPA pups at P14, suggesting that the changes in glial cell density could be due to alterations in the epigenetic developmental program. Finally, no differences in maternal behavior were found. Our results show that female VPA pups exhibit behavioral and inflammatory alterations postnatally, although they have been reported to have normal levels of sociability in adulthood. With our work, we contribute to the understanding of biological mechanisms underlying different effects of VPA on male and female rodents, and we hope to help elucidate whether there are factors increasing susceptibility to ASD in boys and/or resilience in girls.
在自闭症谱系障碍（ASD）中，已有报道称男孩的发病率高于女孩。为了确定在雌性动物中起作用的可能是这种差异潜在原因的生物学机制，我们使用了一种经过广泛验证的ASD小鼠模型：产前暴露于丙戊酸（VPA）。我们发现雌性VPA幼崽出生后的行为改变：出生后第3天（P3）翻正反射的潜伏期延长，以及听觉惊吓反应的习得延迟。我们还分析了VPA组和对照组动物前额叶皮质、海马体和小脑中神经胶质细胞的密度。雌性VPA幼崽在P21至P42期间星形胶质细胞和小胶质细胞的密度出现改变，且每个脑区都有特定的变化动态。我们还发现P14时雌性VPA幼崽小脑内组蛋白3乙酰化水平降低，这表明神经胶质细胞密度的变化可能是由于表观遗传发育程序的改变所致。最后，未发现母性行为存在差异。我们的结果表明，雌性VPA幼崽出生后表现出行为和炎症改变，尽管据报道它们成年后的社交能力水平正常。通过我们的研究，我们有助于理解VPA对雄性和雌性啮齿动物产生不同影响的潜在生物学机制，并且我们希望有助于阐明是否存在增加男孩患ASD易感性和/或女孩恢复力的因素。
