Early 17β-estradiol treatment reduces seizures but not abnormal behaviour in mice with expanded polyalanine tracts in the Aristaless related homeobox gene (ARX).
Early 17β-estradiol treatment reduces seizures but not abnormal behaviour in mice with expanded polyalanine tracts in the Aristaless related homeobox gene (ARX).
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早期 17β-雌二醇治疗可减少癫痫发作，但不会减少 Aristaless 相关同源框基因 (ARX) 中扩展的聚丙氨酸束小鼠的异常行为。
DOI：
10.1016/j.nbd.2021.105329
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发表时间：
2021
影响因子：
6.1
通讯作者：
Shoubridge,Cheryl
中科院分区：
文献类型：
--
作者：
Loring,KaraghE;Mattiske,Tessa;Lee,Kristie;Zysk,Aneta;Jackson,MatildaR;Noebels,JeffreyL;Shoubridge,Cheryl
患有严重智力残疾的儿童难治性癫痫发作的患病率增加。类固醇治疗可以改善癫痫发作的结果，但其机制尚不清楚。在这里，我们证明了在出生后早期短期每日给予外源性类固醇17β-雌二醇（40 ng/g）显著减少癫痫发作的次数和严重程度，但没有改善行为缺陷，在小鼠模型中，Aristaless相关同源框基因（ARX）突变，扩大了第一（PA 1）或第二（PA 2）聚丙氨酸束。与溶剂相比，使用类固醇治疗的PA 1小鼠中观察到的处理时癫痫发作频率（n= 14/治疗/基因型）显著降低（降低32%），PA 2小鼠中的降低幅度更小（降低14%）。在7周龄时评估自发性癫痫发作（n= 7/治疗/基因型），与未治疗小鼠中的癫痫发作活动峰值一致。接受类固醇治疗的PA 1小鼠不再出现最严重的延长性肌阵挛发作。给药的PA 2小鼠癫痫发作较早，随后在出生后癫痫发作减少，在7周龄分析期间完全没有任何癫痫发作。尽管癫痫发作减少，但17β-雌二醇治疗的小鼠在成年期的行为或认知结果没有改善。我们第一次发现，由于Arx突变引起的这些缺陷在癫痫发作前就已经存在，并且不会随着癫痫发作而恶化。ARX是一种转录因子，ArxPA突变小鼠在发育中的胚胎脑中具有失调的转录组谱。在出生后第10天，治疗完成时，RNAseq鉴定出与野生型小鼠相比，在突变小鼠的额叶皮质中有129个基因显著失调（Log 2FC> ± 0.5，P值<0. 05）。该列表反映了在疾病中失调的基因，并且特别丰富了神经发育障碍中的已知基因以及参与信号传导和发育途径的基因。17β-雌二醇处理的突变小鼠的295个基因显著失调，只有23个失调基因在载体和类固醇处理的突变小鼠之间重叠。我们的结论是，17β-雌二醇治疗招募过程和途径，以减少ArxPA突变小鼠癫痫发作的频率和严重程度，但不能精确纠正失调的转录组，也不能改善死亡率或行为和认知缺陷。
Children with severe intellectual disability have an increased prevalence of refractory seizures. Steroid treatment may improve seizure outcomes, but the mechanism remains unknown. Here we demonstrate that short term, daily delivery of an exogenous steroid 17β-estradiol (40 ng/g) in early postnatal life significantly reduced the number and severity of seizures, but did not improve behavioural deficits, in mice modelling mutations in the Aristaless-related homeobox gene (ARX), expanding the first (PA1) or second (PA2) polyalanine tract. Frequency of observed seizures on handling (n= 14/treatment/genotype) were significantly reduced in PA1 (32% reduction) and more modestly reduced in PA2 mice (14% reduction) with steroid treatment compared to vehicle. Spontaneous seizures were assessed (n= 7/treatment/genotype) at 7 weeks of age coinciding with a peak of seizure activity in untreated mice. PA1 mice treated with steroids no longer present with the most severe category of prolonged myoclonic seizures. Treated PA2 mice had an earlier onset of seizures coupled with a subsequent reduction in seizures later in postnatal life, with a complete absence of any seizures during the analysis at 7 weeks of age. Despite the reduction in seizures, 17β-estradiol treated mice showed no improvement in behavioural or cognitive outcomes in adulthood. For the first time we show that these deficits due to mutations inArxare already present before seizure onset and do not worsen with seizures. ARX is a transcription factor andArxPA mutant mice have deregulated transcriptome profiles in the developing embryonic brain. At postnatal day 10, treatment completion, RNAseq identified 129 genes significantly deregulated (Log2FC > ± 0.5,P-value<0.05) in the frontal cortex of mutant compared to wild-type mice. This list reflects genes deregulated in disease and was particularly enriched for known genes in neurodevelopmental disorders and those involved in signalling and developmental pathways. 17β-estradiol treatment of mutant mice significantly deregulated 295 genes, with only 23 deregulated genes overlapping between vehicle and steroid treated mutant mice. We conclude that 17β-estradiol treatment recruits processes and pathways to reduce the frequency and severity of seizures in theArxPA mutant mice but does not precisely correct the deregulated transcriptome nor improve mortality or behavioural and cognitive deficits.