Locomotor Deficiencies and Aberrant Development of Subtype-Specific GABAergic Interneurons Caused by an Unliganded Thyroid Hormone Receptor α1
Locomotor Deficiencies and Aberrant Development of Subtype-Specific GABAergic Interneurons Caused by an Unliganded Thyroid Hormone Receptor α1
复制标题
未配体甲状腺激素受体 α1 引起的运动缺陷和亚型特异性 GABA 能中间神经元的异常发育
DOI：
--
复制
发表时间：
2008
影响因子：
5.3
通讯作者：
B. Vennström
中科院分区：
文献类型：
--
作者：
Karin Wallis;M. Sjögren;M. van Hogerlinden;G. Silberberg;A. Fisahn;K. Nordström;L. Larsson;H. Westerblad;G. Morreale de Escobar;O. Shupliakov;B. Vennström
发育过程中甲状腺激素（TH）缺乏会导致严重和永久性的神经元损伤，但在组织水平上的主要损伤尚未解决。我们已经确定了由甲状腺激素受体α1 （TRα1）突变引起的小鼠运动缺陷，该突变具有可归因于TH亲和力降低的强载脂蛋白活性。这使得鉴定出不同的功能，要么需要母体在胚胎早期发育期间提供TH，要么需要胎儿晚期发育期间有足够的先天激素水平。在这两种情况下，需要在出生后和一生中持续暴露于高水平的TH。激素依赖性与小白蛋白免疫反应性gaba能中间神经元的严重延迟出现和新皮层中calretinin免疫反应性细胞的数量增加有关。这导致快速尖峰的中间神经元数量减少和皮层网络活动的缺陷。胎儿/围产期发育期间由TH供应不足引起的运动缺陷及其与亚型特异性中间神经元的相关性的确定，为地方性克汀病和未经治疗的先天性甲状腺功能减退的神经元后果提供了以前未知的基础，并明确了TRα1是介导这些影响的受体异构体。
Thyroid hormone (TH) deficiency during development causes severe and permanent neuronal damage, but the primary insult at the tissue level has remained unsolved. We have defined locomotor deficiencies in mice caused by a mutant thyroid hormone receptor α1 (TRα1) with potent aporeceptor activity attributable to reduced affinity to TH. This allowed identification of distinct functions that required either maternal supply of TH during early embryonic development or sufficient innate levels of hormone during late fetal development. In both instances, continued exposure to high levels of TH after birth and throughout life was needed. The hormonal dependencies correlated with severely delayed appearance of parvalbumin-immunoreactive GABAergic interneurons and increased numbers of calretinin-immunoreactive cells in the neocortex. This resulted in reduced numbers of fast spiking interneurons and defects in cortical network activity. The identification of locomotor deficiencies caused by insufficient supply of TH during fetal/perinatal development and their correlation with subtype-specific interneurons suggest a previously unknown basis for the neuronal consequences of endemic cretinism and untreated congenital hypothyroidism, and specifies TRα1 as the receptor isoform mediating these effects.
影响因子：
10.5
作者：
Göthe, S;Wang, ZD;Forrest, D
通讯作者：
Forrest, D