Adult onset of type 3 deiodinase deficiency in mice alters brain gene expression and increases locomotor activity.
Adult onset of type 3 deiodinase deficiency in mice alters brain gene expression and increases locomotor activity.
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小鼠成年后出现 3 型脱碘酶缺乏症会改变大脑基因表达并增加运动活动。
DOI：
10.1016/j.psyneuen.2019.104439
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发表时间：
2019
影响因子：
3.7
通讯作者：
Hernandez,Arturo
中科院分区：
文献类型：
--
作者：
Stohn,JPatrizia;Martinez,MElena;StGermain,DonaldL;Hernandez,Arturo
3 型脱碘酶 (DIO3) 的持续性缺失会导致发育中和成年大脑中甲状腺激素作用水平异常升高，从而导致一系列行为异常。为了确定这些表型在多大程度上源自成人大脑中缺乏 DIO3，以及对发育的影响，我们创建了条件性 DIO3 失活的小鼠模型。携带“floxed”Dio3等位基因和他莫昔芬诱导的cre转基因的小鼠在两个月大时被注射他莫昔芬。与注射油的对照组相比，这些小鼠的脑组织中 DIO3 活性降低了 75-80%，重组等位基因表达了 85-95%的 Dio3mRNA。成年 DIO3 缺乏的小鼠在生长、血清甲状腺激素参数或与焦虑和抑郁相关的行为方面没有表现出显着差异。然而，雌性小鼠表现出较高的运动活动和增加的大理石埋藏行为。他们还以性别和区域特异性的方式表现出 T3 依赖性基因和与多动症相关基因表达的相对适度的改变。在甲状腺激素治疗后，DIO3 缺陷雌性小鼠中 T3 调节基因的表达反应通常比雌性对照更明显，而雄性小鼠中则观察到基因型改变的相反效果。成人发病的 DIO3 缺乏的分子和行为表型的程度表明，由结构性 DIO3 缺乏引起的神经系统异常中很大一部分具有发育起源。然而，我们的结果表明，成人大脑中的 DIO3 也会以性别二态性的方式影响行为和对甲状腺激素作用的敏感性。
Constitutive loss of the type 3 deiodinase (DIO3) causes abnormally increased levels of thyroid hormone action in the developing and adult brain, leading to an array of behavioral abnormalities. To determine to what extent those phenotypes derive from a lack of DIO3 in the adult brain, versus developmental consequences, we created a mouse model of conditional DIO3 inactivation. Mice carrying “floxed”Dio3alleles and a tamoxifen-inducible cre transgene were injected with tamoxifen at two months of age. Compared to oil-injected controls, the brain tissue of these mice showed a 75–80% decrease in DIO3 activity and 85–95%Dio3mRNA was expressed from recombinant alleles. Mice with adult DIO3 deficiency did not show significant differences in growth, serum thyroid hormone parameters or behaviors related to anxiety and depression. However, female mice exhibited elevated locomotor activity and increased marble-burying behavior. They also manifested relatively modest alterations in the expression of T3-dependent genes and genes related to hyperactivity in a sex- and region-specific manner. Upon thyroid hormone treatment, the expression response of T3-regulated genes was generally more pronounced in DIO3-deficient female mice than in female controls, while the opposite effect of altered genotype was noticed in males. The extent of the molecular and behavioral phenotypes of adult-onset DIO3 deficiency suggests that a substantial proportion of the neurological abnormalities caused by constitutive DIO3 deficiency has a developmental origin. However, our results show that DIO3 in the adult brain also influences behavior and sensitivity to thyroid hormone action in a sexually dimorphic fashion.