Thyrotropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction
Thyrotropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction
复制标题
促甲状腺素受体敲除改变单胺能神经系统并产生哌醋甲酯敏感的情绪和认知功能障碍
DOI：
10.1016/j.psyneuen.2014.05.021
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发表时间：
2014
影响因子：
3.7
通讯作者：
Nabeshima T
中科院分区：
文献类型：
--
作者：
Mouri A;Hoshino Y;Narusawa S;Ikegami K;Mizoguchi H;Murata Y;Yoshimura T;Nabeshima T
注意力缺陷多动障碍（ADHD）与甲状腺激素抵抗有关，这是一种由甲状腺激素受体β（TRβ）基因突变引起的疾病。TRβ是介导3，3 ′，5-三碘甲状腺原氨酸（T3）下调促甲状腺激素（TSH）表达的关键蛋白。TSH及其受体（TSHR）的失调与ADHD的病理生理学有关，但TSHR的作用仍然难以捉摸。在这里，我们阐明了TSHR在与单胺能神经系统相关的情感和认知功能中的新作用。TSHR基因敲除小鼠表现出ADHD的表型，如多动症，冲动，社交能力下降和攻击性增加，以及短期记忆和物体识别记忆受损。哌醋甲酯（1，5和10毫克/公斤）的管理逆转冲动，侵略和物体识别记忆障碍。在基因敲除小鼠中，在某些脑区观察到单胺能变化，包括3-甲氧基-4-羟基苯乙二醇/去甲肾上腺素的比例降低和高香草酸/多巴胺的比例增加，同时额叶皮质中去甲肾上腺素转运蛋白的表达增加。当TSH被T3的超生理给药完全抑制的成年小鼠，在TSHR KO小鼠的一些行为和神经系统的变化也被观察到，这表明这些变化不是由于发育性甲状腺功能减退症引起的失活的TSHR，但TSH-TSHR通路本身的损失。综上所述，目前的研究结果表明，TSHR在ADHD的行为和神经表型中的新作用。
Attention deficit/hyperactivity disorder (ADHD) has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor β (TRβ) gene. TRβ is a key protein mediating down-regulation of thyrotropin (TSH) expression by 3,3′,5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD but the role of TSHR remains elusive. Here, we clarified a novel role for TSHR in emotional and cognitive functions related to monoaminergic nervous systems. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate (1, 5 and 10 mg/kg) reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH-TSHR pathway itself. Taken together, the present findings suggest a novel role for TSHR in behavioral and neurological phenotypes of ADHD.