Functional MHCI deficiency in mice causes ADHD-like behaviors with increased accumbal dopamine D1 receptor expression
Functional MHCI deficiency in mice causes ADHD-like behaviors with increased accumbal dopamine D1 receptor expression
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小鼠功能性 MHCI 缺陷会导致 ADHD 样行为，并导致累积多巴胺 D1 受体表达增加
DOI：
10.1016/j.bbi.2021.05.015
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发表时间：
2021
影响因子：
15.1
通讯作者：
Murakami G
中科院分区：
文献类型：
--
作者：
Meng H;Suenaga T;Edamura M;Fukuda A;Ishida Y;Nakahara D;Murakami G
不适当的突触发育被认为是神经发育障碍的潜在机制，包括注意力缺陷多动障碍（ADHD）。主要组织相容性复合物I类（MHCI），一种由脑中神经元表达的免疫相关分子，调节突触发育;然而，MHCI在这些疾病中的参与仍然难以捉摸。我们评估了由β 2 m −/− Tap 1 −/−双敲除小鼠诱导的功能性MHCI缺陷是否会导致类似于神经发育障碍中所见的异常。我们发现，功能性MHCI缺乏导致运动过度活跃，运动冲动和注意力缺陷，ADHD的三个主要症状。相比之下，这些小鼠表现出正常的空间学习，行为灵活性，社会行为和感觉运动整合。在多巴胺系统的分析，上调多巴胺D1受体（D1 R）的表达在脑桥核和更大的运动反应D1 R激动剂SKF 81297被发现在功能性MHCI缺陷小鼠。用于治疗ADHD患者的低剂量哌醋甲酯减轻了三种行为症状，并抑制了小鼠D1 R表达的中型棘状神经元中的c-Fos表达。这些发现揭示了MHCI在ADHD的三个主要症状中的意想不到的作用，并可能为ADHD的发病机制提供新的里程碑
Inappropriate synaptic development has been proposed as a potential mechanism of neurodevelopmental disorders, including attention-deficit hyperactivity disorder (ADHD). Major histocompatibility complex class I (MHCI), an immunity-associated molecule expressed by neurons in the brain, regulates synaptic development; however, the involvement of MHCI in these disorders remains elusive. We evaluated whether functional MHCI deficiency induced byβ2m−/−Tap1−/−double-knockout in mice leads to abnormalities akin to those seen in neurodevelopmental disorders. We found that functional MHCI deficiency induced locomotor hyperactivity, motor impulsivity, and attention deficits, three major symptoms of ADHD. In contrast, these mice showed normal spatial learning, behavioral flexibility, social behavior, and sensorimotor integration. In the analysis of the dopamine system, upregulation of dopamine D1 receptor (D1R) expression in the nucleus accumbens and a greater locomotor response to D1R agonist SKF 81297 were found in the functional MHCI-deficient mice. Low-dose methylphenidate, used for the treatment of ADHD patients, alleviated the three behavioral symptoms and suppressed c-Fos expression in the D1R-expressing medium spiny neurons of the mice. These findings reveal an unexpected role of MHCI in three major symptoms of ADHD and may provide a novel landmark in the pathogenesis of ADHD