Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a.
Circadian Rhythms and Sleep Are Dependent Upon Expression Levels of Key Ubiquitin Ligase Ube3a.
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DOI：
10.3389/fnbeh.2022.837523
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发表时间：
2022
影响因子：
3
通讯作者：
Johnson CH
中科院分区：
文献类型：
--
作者：
Shi SQ;Mahoney CE;Houdek P;Zhao W;Anderson MP;Zhuo X;Beaudet A;Sumova A;Scammell TE;Johnson CH
正常的神经发育需要精确表达关键的泛素连接酶基因Ube3a。比较新生成的Ube3a下调小鼠模型（Angelman综合征模型）和Ube3a上调小鼠模型（自闭症模型），我们发现Ube3a基因剂量对与昼夜节律相关的表型（包括运动活动量）的相互影响。与一般神经元的结果一致，我们发现Ube3a在视交叉上核（SCN）的神经元中有印记，SCN是大脑节律的起搏器，尽管其他声称SCN神经元在某种程度上例外于这些印记规则。此外，缺乏ube3a的小鼠在黑暗期后期缺乏典型的清醒下降，并且对睡眠剥夺的反应迟钝。根据行为测试和应激激素的测量，ube3a缺陷小鼠在光照下的身体活动抑制不是由于焦虑；应激激素的量化可能提供了由Ube3a缺乏引起的睡眠改变和记忆缺陷的机制联系，并可作为评估Angelman综合征潜在治疗方法的易于测量的生物标志物。我们得出结论，减少Ube3a基因剂量不仅影响神经发育，还影响睡眠模式和昼夜节律。
Normal neurodevelopment requires precise expression of the key ubiquitin ligase gene Ube3a. Comparing newly generated mouse models for Ube3a downregulation (models of Angelman syndrome) vs. Ube3a upregulation (models for autism), we find reciprocal effects of Ube3a gene dosage on phenotypes associated with circadian rhythmicity, including the amount of locomotor activity. Consistent with results from neurons in general, we find that Ube3a is imprinted in neurons of the suprachiasmatic nuclei (SCN), the pacemaking circadian brain locus, despite other claims that SCN neurons were somehow exceptional to these imprinting rules. In addition, Ube3a-deficient mice lack the typical drop in wake late in the dark period and have blunted responses to sleep deprivation. Suppression of physical activity by light in Ube3a-deficient mice is not due to anxiety as measured by behavioral tests and stress hormones; quantification of stress hormones may provide a mechanistic link to sleep alteration and memory deficits caused by Ube3a deficiency, and serve as an easily measurable biomarker for evaluating potential therapeutic treatments for Angelman syndrome. We conclude that reduced Ube3a gene dosage affects not only neurodevelopment but also sleep patterns and circadian rhythms.
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影响因子：
3.7
作者：
Grier MD;Carson RP;Lagrange AH
通讯作者：
Lagrange AH
影响因子：
2.9
作者：
Morin LP;Hefton S;Studholme KM
通讯作者：
Studholme KM
影响因子：
5.6
作者：
Espana, Rodrigo A.;Scammell, Thomas E.
通讯作者：
Scammell, Thomas E.
影响因子：
2.9
作者：
EDGAR, DM;KILDUFF, TS;DEMENT, WC
通讯作者：
DEMENT, WC
DOI：
10.1002/aur.2267
发表时间：
2020-03
期刊：
Autism research : official journal of the International Society for Autism Research
影响因子：
--
作者：
Dodge A;Peters MM;Greene HE;Dietrick C;Botelho R;Chung D;Willman J;Nenninger AW;Ciarlone S;Kamath SG;Houdek P;Sumová A;Anderson AE;Dindot SV;Berg EL;O'Geen H;Segal DJ;Silverman JL;Weeber EJ;Nash KR
通讯作者：
Nash KR