Williams Olivia O F, Coppolino Madeleine, Micelli Cecilia B, McCallum Ryan T, Henry-Duru Paula T, Manduca Joshua D, Lalonde Jasmin, Perreault Melissa L
Department of Biomedical Sciences, University of Guelph, 50 Stone Rd. E., Guelph, Ontario N1G 2W1, Canada.
Department of Biomedical Sciences, University of Guelph, 50 Stone Rd. E., Guelph, Ontario N1G 2W1, Canada.
Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jan 10;136:111222. doi: 10.1016/j.pnpbp.2024.111222. Epub 2024 Dec 17.
There are substantial differences in the characteristics of males and females with an autism spectrum disorder (ASD), yet there is little knowledge surrounding the mechanistic underpinnings of these differences. The valproic acid (VPA) rodent model is based upon the human fetal valproate spectrum disorder, which is associated with increased risk of developing ASD. This model, which displays significant social, learning, and memory alterations, has therefore been widely used to further our understanding of specific biological features of ASD. However, to date, almost all of the studies employing this model have used male rodents. To fill this knowledge gap, we evaluated sex differences for neuronal activity, morphology, and glycogen synthase kinase-3 (GSK-3) signaling in primary cortical (CTX) and hippocampal (HIP) neurons prepared from rats exposed to VPA in utero. In vivo, sex-specific VPA-induced alterations in the frontal CTX transcriptome at birth were also determined. Overall, VPA induced more robust changes in neuronal function and structure in the CTX than in the HIP. Male- and female-derived primary CTX neurons from rats exposed to prenatal VPA had elevated activity and showed more disorganized firing. In the HIP, only the female VPA neurons showed elevated firing, while the male VPA neurons exhibited disorganized activity. Dendritic arborization of CTX neurons from VPA rats was less complex in both sexes, though this was more pronounced in the females. Conversely, both female and male HIP neurons from VPA rats showed elevated complexity distal to the soma. Female VPA CTX neurons also had an elevated number of dendritic spines. The relative activity of the α and β isoforms of GSK-3 were suppressed in both female and male VPA CTX neurons, with no changes in the HIP neurons. On postnatal day 0, alterations in CTX genes associated with neuropeptides (e.g., penk, pdyn) and receptors (e.g., drd1, adora2a) were seen in both sexes, though they were downregulated in females and upregulated in males. Together these findings suggest that substantial sex differences in neuronal structure and function in the VPA model may have relevance to the reported sex differences in idiopathic ASD.
患有自闭症谱系障碍（ASD）的男性和女性在特征上存在显著差异，但对于这些差异的机制基础却知之甚少。丙戊酸（VPA）啮齿动物模型基于人类胎儿丙戊酸盐谱系障碍，该障碍与患ASD的风险增加有关。此模型表现出显著的社交、学习和记忆改变，因此已被广泛用于增进我们对ASD特定生物学特征的理解。然而，迄今为止，几乎所有采用该模型的研究都使用雄性啮齿动物。为填补这一知识空白，我们评估了从子宫内暴露于VPA的大鼠制备的原代皮质（CTX）和海马（HIP）神经元中神经元活动、形态以及糖原合酶激酶-3（GSK-3）信号传导的性别差异。在体内，还确定了出生时VPA诱导的额叶CTX转录组中的性别特异性改变。总体而言，VPA在CTX中诱导的神经元功能和结构变化比在HIP中更强烈。来自产前暴露于VPA的大鼠的雄性和雌性原代CTX神经元活性升高，且放电更紊乱。在HIP中，只有雌性VPA神经元放电增加，而雄性VPA神经元表现出紊乱的活动。VPA大鼠的CTX神经元的树突分支在两性中都不太复杂，不过在雌性中更明显。相反，VPA大鼠的雌性和雄性HIP神经元在胞体远端都表现出复杂性增加。雌性VPA CTX神经元的树突棘数量也增加。GSK-3的α和β亚型的相对活性在雌性和雄性VPA CTX神经元中均受到抑制，而在HIP神经元中没有变化。在出生后第0天，两性中均可见与神经肽（如penk、pdyn）和受体（如drd1、adora2a）相关的CTX基因改变，不过在雌性中下调，在雄性中上调。这些发现共同表明，VPA模型中神经元结构和功能的显著性别差异可能与特发性ASD中报道的性别差异相关。
