Iacobas D A, Iacobas S, Chachua T, Goletiani C, Sidyelyeva G, Velíšková J, Velíšek L
Department of Pathology, New York Medical College, Valhalla, NY, USA.
J Neuroendocrinol. 2013 Nov;25(11):964-79. doi: 10.1111/jne.12061.
Prenatal exposure to corticosteroids has long-term postnatal somatic and neurodevelopmental consequences. Animal studies indicate that corticosteroid exposure-associated alterations in the nervous system include hypothalamic function. Infants with infantile spasms, a devastating epileptic syndrome of infancy with characteristic spastic seizures, chaotic irregular waves on interictal electroencephalogram (hypsarhythmia) and mental deterioration, have decreased concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in cerebrospinal fluid, strongly suggesting hypothalamic dysfunction. We have exploited this feature to develop a model of human infantile spasms by using repeated prenatal exposure to betamethasone and a postnatal trigger of developmentally relevant spasms with NMDA. The spasms triggered in prenatally primed rats are more severe compared to prenatally saline-injected ones and respond to ACTH, a treatment of choice for infantile spasms in humans. Using autoradiography and immunohistochemistry, we have identified a link between the spasms in our model and the hypothalamus, especially the arcuate nucleus. Transcriptomic analysis of the arcuate nucleus after prenatal priming with betamethasone but before trigger of spasms indicates that prenatal betamethasone exposure down-regulates genes encoding several important proteins participating in glutamatergic and GABAergic transmission. Interestingly, there were significant sex-specific alterations after prenatal betamethasone in synapse-related gene expression but no such sex differences were found in prenatally saline-injected controls. A pairwise relevance analysis revealed that, although the synapse gene expression in controls was independent of sex, these genes form topologically distinct gene fabrics in males and females and these fabrics are altered by betamethasone in a sex-specific manner. These findings may explain the sex differences with respect to both normal behaviour and the occurrence and severity of infantile spasms. Changes in transcript expression and their coordination may contribute to a molecular substrate of permanent neurodevelopmental changes (including infantile spasms) found after prenatal exposure to corticosteroids.
产前暴露于皮质类固醇会对产后的躯体和神经发育产生长期影响。动物研究表明，与皮质类固醇暴露相关的神经系统改变包括下丘脑功能。患有婴儿痉挛症的婴儿，这是一种具有特征性痉挛发作、发作间期脑电图上有混沌不规则波（高峰失律）和智力衰退的严重婴儿癫痫综合征，其脑脊液中促肾上腺皮质激素（ACTH）和皮质醇浓度降低，强烈提示下丘脑功能障碍。我们利用这一特征，通过反复产前暴露于倍他米松，并在产后用N-甲基-D-天冬氨酸（NMDA）触发与发育相关的痉挛，建立了人类婴儿痉挛症模型。与产前注射生理盐水的大鼠相比，产前致敏大鼠引发的痉挛更严重，且对ACTH有反应，ACTH是人类婴儿痉挛症的一种首选治疗方法。通过放射自显影和免疫组织化学，我们已经确定了我们模型中的痉挛与下丘脑，特别是弓状核之间的联系。在产前用倍他米松致敏但在痉挛触发之前对弓状核进行转录组分析表明，产前倍他米松暴露下调了编码参与谷氨酸能和γ-氨基丁酸能传递的几种重要蛋白质的基因。有趣的是，产前倍他米松暴露后，突触相关基因表达存在显著的性别特异性改变，但在产前注射生理盐水的对照组中未发现此类性别差异。成对相关性分析显示，虽然对照组中的突触基因表达与性别无关，但这些基因在雄性和雌性中形成拓扑结构不同的基因网络，并且这些网络会被倍他米松以性别特异性方式改变。这些发现可能解释了正常行为以及婴儿痉挛症的发生和严重程度方面的性别差异。转录本表达的变化及其协调性可能有助于为产前暴露于皮质类固醇后发现的永久性神经发育变化（包括婴儿痉挛症）提供分子基础。
