Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology.
Striatal Signaling Regulated by the H3R Histamine Receptor in a Mouse Model of tic Pathophysiology.
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DOI：
10.1016/j.neuroscience.2018.09.035
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发表时间：
2018-11-10
期刊：
影响因子：
3.3
通讯作者：
Pittenger C
中科院分区：
文献类型：
--
作者：
Rapanelli M;Frick L;Jindachomthong K;Xu J;Ohtsu H;Nairn AC;Pittenger C
组胺失调已被确定为抽动障碍的一种罕见的遗传原因，小鼠与组氨酸脱羧酶（Hdc）基因敲除代表了一个有前途的模型，这种病理生理。然而，组胺系统的改变如何导致神经精神疾病仍不清楚。H3 R组胺受体在Hdc KO小鼠的纹状体中升高，并且作用于背侧纹状体的H3 R激动剂在模型中触发抽动样运动。在野生型小鼠中，背侧纹状体中的H3 R差异调节表达D1 R多巴胺受体的纹状体黑质中棘神经元（dMSN）和表达D2 R多巴胺受体的纹状体锥体MSNs（iMSN）中的MAPK和Akt信号。在此，我们检查了H3 R激动剂处理对Hdc-KO模型中MSN信号传导的影响。在dMSN中，MAPK信号传导在Hdc-KO模型中在基线时升高，类似于WT动物中H3 R活化后所见。类似地，在iMSN中，Akt磷酸化在KO模型中在基线处减少，类似于WT动物中H3 R活化后所见。Hdc-KO小鼠中的H3 R活化进一步增强了iMSN中Akt磷酸化的基线效应，但减弱了dMSN中MAPK信号传导的异常。这些观察结果支持Hdc-KO模型中上调的H3 R受体的组成性活性介导基线MSN信号传导中观察到的改变的假设;但是H3 R的进一步激活（其在模型中产生抽动样重复运动）具有更复杂的影响。
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 model of this pathophysiology. How alterations in the histamine system lead to neuropsychiatric disease, however, remains unclear. The H3R histamine receptor is elevated in the striatum of Hdc KO mice, and H3R agonists, acting in the dorsal striatum, trigger tic-like movements in the model. In wild-type mice, H3R in the dorsal striatum differentially regulates MAPK and Akt signaling in D1R dopamine receptor-expressing striatonigral medium spiny neurons (dMSNs) and D2R dopamine receptor-expressing striatopallidal MSNs (iMSNs). Here we examined the effects of H3R agonist treatment on MSN signaling in the Hdc-KO model. In dMSNs, MAPK signaling was elevated at baseline in the Hdc-KO model, resembling what is seen after H3R activation in WT animals. Similarly, in iMSNs, Akt phosphorylation was reduced at baseline in the KO model, resembling what is seen after H3R activation in WT animals. H3R activation in Hdc-KO mice further enhanced the baseline effect on Akt phosphorylation in iMSNs but attenuated the abnormality in MAPK signaling in dMSNs. These observations support the hypothesis that constitutive activity of upregulated H3R receptors in the Hdc-KO model mediates the observed alterations in baseline MSN signaling; but further activation of H3R, which produces tic-like repetitive movements in the model, has more complex effects.
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