Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism
Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism
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DOI：
10.1186/s13041-020-00649-7
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发表时间：
2020-08-10
期刊：
影响因子：
3.6
通讯作者：
Yang, Yi-Mei
中科院分区：
文献类型：
--
作者：
Chao, Owen Y.;Pathak, Salil S.;Yang, Yi-Mei
多巴胺(DA)系统对奖赏动机行为有深远的影响，并与神经发育障碍密切相关，如自闭症谱系障碍(ASD)。虽然自闭症患者存在DA缺陷，但在ASD中DA通路是如何改变的，以及DA是否可以被用作ASD的潜在治疗药物，目前还没有很好的定义。为此，我们采用了表型和遗传性ASD模型，即Black和Tan brachyury T(+)Itpr3(Tf)/J(BTBR)小鼠和脆性X智力低下1基因敲除(Fmr1-KO)小鼠。用酪氨酸羟化酶(TH)标记多巴胺能神经元的免疫组织化学染色显示，与C57BL/6J野生型小鼠相比，BTBR小鼠黑质、腹侧被盖区和背侧纹状体中TH的表达总体上减少。相反，Fmr1-KO动物没有表现出这种改变，但纹状体中TH阳性轴突的形态异常，具有更高的复杂性和更低的质地。两株大鼠纹状体多巴胺转运体(DAT)表达减少，囊泡型谷氨酸转运体1(VGLUT1，谷氨酸能终末标记物)与TH信号之间的空间耦合增强，而谷氨酸脱羧酶67(GAD67)定量的GABA能神经元保持完整。鼻腔注射DA可改善BTBR小鼠在非选择性注意、基于对象的注意和社交接近方面的缺陷，这可能是通过提高纹状体TH水平来实现的。在Fmr1-KO动物中，鼻内应用DA可减轻其社会新颖性的损害，与纹状体TH蛋白减少有关。这些结果表明，尽管两种ASD模型的DA系统发生了不同的改变，但鼻腔注射DA有效地纠正了它们的行为表型，这可能为不同类型的ASD提供一种有前途的治疗方法。
The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found in autistic patients, it is not well defined how the DA pathways are altered in ASD and whether DA can be utilized as a potential therapeutic agent for ASD. To this end, we employed a phenotypic and a genetic ASD model, i.e., Black and Tan BRachyury T(+)Itpr3(tf)/J (BTBR) mice and Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction in the TH expression in the substantia nigra, ventral tegmental area and dorsal striatum of BTBR mice, as compared to C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did not show such an alteration but displayed abnormal morphology of TH-positive axons in the striatum with higher "complexity" and lower "texture". Both strains exhibited decreased expression of striatal dopamine transporter (DAT) and increased spatial coupling between vesicular glutamate transporter 1 (VGLUT1, a label for glutamatergic terminals) and TH signals, while GABAergic neurons quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration of DA rescued the deficits in non-selective attention, object-based attention and social approaching of BTBR mice, likely by enhancing the level of TH in the striatum. Application of intranasal DA to Fmr1-KO animals alleviated their impairment of social novelty, in association with reduced striatal TH protein. These results suggest that although the DA system is modified differently in the two ASD models, intranasal treatment with DA effectively rectifies their behavioral phenotypes, which may present a promising therapy for diverse types of ASD.