The histidine decarboxylase model of tic pathophysiology: a new focus on the histamine H3 receptor.
The histidine decarboxylase model of tic pathophysiology: a new focus on the histamine H3 receptor.
复制标题
抽动症病理生理学的组氨酸脱羧酶模型：组胺 H3 受体的新焦点。
DOI：
10.1111/bph.14606
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Pittenger,Christopher
中科院分区：
文献类型：
--
作者：
Pittenger,Christopher
十年前，在一个高密度家系中进行的一项里程碑式的遗传学研究表明，组胺失调是多发性抽动症和其他抽动障碍的罕见原因，该研究表明组氨酸脱羧酶(HDC)基因的亚型突变是一种罕见但高外显性的遗传原因。对Hdc基因敲除(KO)小鼠的研究已经证实，这种突变导致与抽动相关的行为和神经化学异常，与在患者中看到的情况相似，从而验证了KO作为抽动病理生理学的潜在信息模型。最近的研究集中在组胺H3受体在这一模型中的潜在作用，以及与抽动障碍和相关的神经精神疾病的关联。HdcKO小鼠纹状体内H3受体表达上调。由于H3受体在没有配体的情况下具有结构性活性，尽管这些小鼠缺乏神经递质组胺，但这种受体上调可能具有显著的细胞效应。野生型小鼠体内H3受体的激活调节纹状体中棘神经元(MSN)的信号传递，该神经元与多巴胺受体信号传递非线性相互作用。HdcKO小鼠MSN的基线信号变化类似于野生型动物H3受体激动剂治疗后的变化。H3受体激动剂在KOS中的治疗进一步加剧了大多数这些信号异常，并产生了行为刻板印象。总而言之，这些数据表明了一个有趣的假设，即上调调控的H3受体的结构性信号解释了这些动物中看到的许多分子和行为异常。链接文章本文是21世纪新用途主题部分的一部分。要查看本节中的其他文章，请访问http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc
Histamine dysregulation was implicated as a rare cause of Tourette syndrome and other tic disorders a decade ago by a landmark genetic study in a high density family pedigree, which implicated a hypomorphic mutation in thehistidine decarboxylase(Hdc) gene as a rare but high penetrance genetic cause. Studies inHdcknockout (KO) mice have confirmed that this mutation causes tic‐relevant behavioural and neurochemical abnormalities that parallel what is seen in patients and thus validate the KO as a potentially informative model of tic pathophysiology. Recent studies have focused on the potential role of the histamine H3receptor in this model, and by association in tic disorders and related neuropsychiatric conditions. The H3receptor is up‐regulated in the striatum inHdcKO mice. As the H3receptor has constitutive activity in the absence of ligand, this receptor up‐regulation may have significant cellular effects despite the absence of neurotransmitter histamine in these mice. Activation in vivo of H3receptors in wild type mice regulates signalling in striatal medium spiny neurons (MSNs) that interacts non‐linearly with dopamine receptor signalling. Baseline signalling alterations in MSNs inHdcKO mice resemble those seen after H3receptor agonist treatment in wild type animals. H3receptor agonist treatment in the KOs further accentuates most of these signalling abnormalities and produces behavioural stereotypy. Together, these data suggest the intriguing hypothesis that constitutive signalling by up‐regulated H3receptors explains many of the molecular and behavioural abnormalities seen in these animals.Linked ArticlesThis article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc