Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders.
Histamine H3R receptor activation in the dorsal striatum triggers stereotypies in a mouse model of tic disorders.
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DOI：
10.1038/tp.2016.290
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发表时间：
2017-01-24
影响因子：
6.8
通讯作者：
Pittenger C
中科院分区：
文献类型：
--
作者：
Rapanelli M;Frick L;Pogorelov V;Ohtsu H;Bito H;Pittenger C
抽动障碍影响约5%的人口，并且经常与强迫症、自闭症和注意力缺陷障碍共病。组胺失调已被确定为抽动障碍的一种罕见的遗传原因，与组氨酸脱羧酶（Hdc）基因敲除小鼠代表一个有前途的病理生理学接地模型。然而，组胺系统的改变是如何导致抽搐和其他神经精神病理的，目前尚不清楚。我们发现Hdc基因敲除小鼠纹状体中组胺H3受体的表达升高。H3受体具有显著的基础活性，即使在没有配体的情况下，因此可以在该敲除模型中调节纹状体功能。我们使用特异性激动剂探测H3 R功能。H3激动剂R-氨甲基组胺（RAMH）和immepip在KO小鼠中产生行为刻板，但在对照组中没有。H3激动剂治疗在KO小鼠中升高纹状体内多巴胺，但在对照中不升高。这与背侧纹状体中rpS 6磷酸化水平升高有关，rpS 6是神经活动的敏感标志物。我们使用了一种新的化学发生策略，以证明这种背侧纹状体的活动是必要的和足够的刻板的发展：当RAMH-激活的细胞在背侧纹状体化学发生激活（在RAMH的情况下），刻板是重演KO动物，当他们沉默的RAMH产生刻板的能力被封锁。这些结果确定了背侧纹状体中的H3受体作为重复行为病理学的贡献者。
Tic disorders affect ~5% of the population and are frequently comorbid with obsessive-compulsive disorder, autism, and attention deficit disorder. Histamine dysregulation has been identified as a rare genetic cause of tic disorders; mice with a knockout of the histidine decarboxylase (Hdc) gene represent a promising pathophysiologically grounded model. How alterations in the histamine system lead to tics and other neuropsychiatric pathology, however, remains unclear. We found elevated expression of the histamine H3 receptor in the striatum of Hdc knockout mice. The H3 receptor has significant basal activity even in the absence of ligand and thus may modulate striatal function in this knockout model. We probed H3R function using specific agonists. The H3 agonists R-aminomethylhistamine (RAMH) and immepip produced behavioral stereotypies in KO mice, but not in controls. H3 agonist treatment elevated intra-striatal dopamine in KO mice, but not in controls. This was associated with elevations in phosphorylation of rpS6, a sensitive marker of neural activity, in the dorsal striatum. We used a novel chemogenetic strategy to demonstrate that this dorsal striatal activity is necessary and sufficient for the development of stereotypy: when RAMH-activated cells in the dorsal striatum were chemogenetically activated (in the absence of RAMH), stereotypy was recapitulated in KO animals, and when they were silenced the ability of RAMH to produce stereotypy was blocked. These results identify the H3 receptor in the dorsal striatum as a contributor to repetitive behavioral pathology.
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影响因子：
16.2
作者：
Cowansage, Kiriana K.;Shuman, Tristan;Dillingham, Blythe C.;Chang, Allene;Golshani, Peyman;Mayford, Mark
通讯作者：
Mayford, Mark
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通讯作者：
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作者：
Dere, E;De Souza-Silva, MA;Huston, JP
通讯作者：
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影响因子：
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作者：
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通讯作者：
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