Data_Sheet_1_White matter abnormalities in the Hdc knockout mouse, a model of tic and OCD pathophysiology.PDF

IntroductionAn inactivating mutation in the histidine decarboxylase gene (Hdc) has been identified as a rare but high-penetrance genetic cause of Tourette syndrome (TS). TS is a neurodevelopmental syndrome characterized by recurrent motor and vocal tics; it is accompanied by structural and functional abnormalities in the cortico-basal ganglia circuitry. Hdc, which is expressed both in the posterior hypothalamus and peripherally, encodes an enzyme required for the biosynthesis of histamine. Hdc knockout mice (Hdc-KO) functionally recapitulate this mutation and exhibit behavioral and neurochemical abnormalities that parallel those seen in patients with TS.
Materials and methodsWe performed exploratory RNA-seq to identify pathological alterations in several brain regions in Hdc-KO mice. Findings were corroborated with RNA and protein quantification, immunohistochemistry, and ex vivo brain imaging using MRI.
ResultsExploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain ex vivo diffusion tensor imaging (DTI), which revealed reduced fractional anisotropy (FA) in the dorsal striatum.
DiscussionWhile the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with tics. The Hdc-KO model may represent a powerful system in which to examine the developmental mechanisms underlying this abnormality.

引言：组氨酸脱羧酶基因（histidine decarboxylase, Hdc）的失活突变已被证实为抽动秽语综合征（Tourette syndrome, TS）的一种罕见但外显率高的遗传病因。抽动秽语综合征属于神经发育综合征，以反复发作的运动性和发声性抽动为核心特征，患者的皮质-基底节环路存在结构与功能异常。Hdc在下丘脑后部及外周组织中均有表达，其编码的酶是组胺生物合成所必需的。Hdc敲除小鼠（Hdc-KO）在功能上重现了该突变表型，并表现出与TS患者高度相似的行为学与神经化学异常。

材料与方法：本研究通过探索性RNA测序（RNA-seq）分析Hdc-KO小鼠多个脑区的病理改变，并通过RNA与蛋白定量、免疫组织化学以及离体磁共振成像（MRI）脑扫描对实验结果进行验证。

结果：探索性RNA测序分析意外发现，该小鼠背侧纹状体中与少突胶质细胞及髓鞘生成相关的基因表达显著上调。该结论通过定量聚合酶链反应（qPCR）、免疫染色与免疫印迹得到了独立验证。上述结果提示纹状体存在髓鞘形成异常。为在完整小鼠脑中验证这一发现，我们开展了全脑离体弥散张量成像（diffusion tensor imaging, DTI），结果显示背侧纹状体的各向异性分数（fractional anisotropy, FA）显著降低。

讨论：尽管目前针对TS患者的弥散张量成像研究较为匮乏，但本研究结果与抽动患者皮质下行投射受损的相关临床发现高度一致。Hdc-KO模型或可成为研究该异常背后发育机制的有力实验系统。