Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats
Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats
复制标题
DOI：
10.1210/en.2015-1643
复制
发表时间：
2016-02-01
期刊：
影响因子：
4.8
通讯作者：
Wood, C.
中科院分区：
文献类型：
--
作者：
Gilbert, M. E.;Sanchez-Huerta, K.;Wood, C.
在大脑发育的关键阶段，严重的甲状腺激素(TH)缺乏会导致不可逆转的神经和认知损害。造成这一现象的机制可能是多因素的，目前还不完全清楚。在这里，我们追求的可能性是，一个重要的因素是，这影响了基础和活动依赖的神经营养因子在大脑区域的表达，这些区域对神经加工至关重要。在发育过程中逐步暴露于丙基硫氧嘧啶(PTU)可导致新生儿整个海马区神经生长因子(NGF)mRNA表达的剂量依赖性减少。这些基础表达的变化一直持续到成年，尽管血液中的甲状腺功能恢复正常。与PTU诱导的几个基因的基础表达减少相反，发育性PTU治疗显著降低了成年后神经营养因子和相关基因(BDNF(T)、BDNF(Iv)、Arc和Klf9)的活性依赖性表达，并伴随着基于海马体的学习障碍。这些数据表明，发育过程中轻微的TH不足不仅会减少持续到成年的重要神经营养因子的表达，还会严重限制这些基因的活性依赖诱导。考虑到这些神经营养因子对在发育和成熟的大脑中塑造结构和功能突触结构的重要性，这些可塑性机制中的TH介导的缺陷很可能导致伴随着发育TH妥协的认知缺陷。
Severe thyroid hormone (TH) deficiency during critical phases of brain development results in irreversible neurological and cognitive impairments. The mechanisms accounting for this are likely multifactorial, and are not fully understood. Here we pursue the possibility that one important element is that TH affects basal and activity-dependent neurotrophin expression in brain regions important for neural processing. Graded exposure to propylthiouracil (PTU) during development produced dose-dependent reductions in mRNA expression of nerve growth factor (Ngf) in whole hippocampus of neonates. These changes in basal expression persisted to adulthood despite the return to euthyroid conditions in blood. In contrast to small PTU-induced reductions in basal expression of several genes, developmental PTU treatment dramatically reduced the activity-dependent expression of neurotrophins and related genes (Bdnf(t), Bdnf(iv), Arc, and Klf9) in adulthood and was accompanied by deficits in hippocampal-based learning. These data demonstrate that mild TH insufficiency during development not only reduces expression of important neurotrophins that persists into adulthood but also severely restricts the activity-dependent induction of these genes. Considering the importance of these neurotrophins for sculpting the structural and functional synaptic architecture in the developing and the mature brain, it is likely that TH-mediated deficits in these plasticity mechanisms contribute to the cognitive deficiencies that accompany developmental TH compromise.