Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States; Department of Psychiatry, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States; Department of Neurology, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States.
Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, United States; Department of Neurology, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States; Department of Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205, United States.
Exp Neurol. 2018 Sep;307:74-81. doi: 10.1016/j.expneurol.2018.05.019. Epub 2018 May 18.
We tested the claim that the dopaminergic dysfunction of Rett Syndrome (RTT) also occurs in Mecp2-deficient mice that serve as a model of the syndrome. We used positron emission tomography (PET) to image dopamine D receptors (DR) and transporters (DAT) in women with RTT and in Mecp2-deficient mice, and DR and DR density was measured in postmortem human tissue by autoradiography. Results showed 1) significantly reduced DR density in the striatum of women with RTT compared to control subjects. 2) PET imaging of mouse striatum similarly demonstrated significant reductions in DR density of 7-10 week-old hemizygous (Mecp2-null) and heterozygous (HET) mice compared to wild type (WT) mice. With age, the density of DR declined in WT mice but not HET mice. 3) In contrast, postmortem autoradiography revealed no group differences in the density of DR and DR in the caudate and putamen of RTT versus normal control subjects. 4) In humans and in the mouse model, PET revealed only marginal group differences in DAT. The results confirm that dopaminergic dysfunction in RTT is also present in Mecp2-deficient mice and that reductions in DR more likely explain the impaired ambulation and progressive rigidity observed rather than alterations in DAT.
我们验证了这样一种说法，即雷特综合征（RTT）的多巴胺能功能障碍也存在于作为该综合征模型的 Mecp2 缺陷小鼠中。我们使用正电子发射断层扫描（PET）对 RTT 女性和 Mecp2 缺陷小鼠的多巴胺 D 受体（DR）和转运蛋白（DAT）进行成像，并通过放射自显影术测量死后人类组织中的 DR 和 DR 密度。结果表明：1）与对照组相比，RTT 女性纹状体中的 DR 密度显著降低。2）对小鼠纹状体的 PET 成像同样表明，与野生型（WT）小鼠相比，7-10 周龄的半合子（Mecp2 缺失）和杂合子（HET）小鼠的 DR 密度显著降低。随着年龄的增长，WT 小鼠的 DR 密度下降，但 HET 小鼠的 DR 密度没有下降。3）相比之下，RTT 与正常对照组相比，死后 autoradiography 并未显示纹状体和尾状核和壳核中 DR 和 DR 密度的组间差异。4）在人类和小鼠模型中，PET 仅显示 DAT 存在微小的组间差异。这些结果证实，Mecp2 缺陷小鼠中也存在多巴胺能功能障碍，并且 DR 的减少更可能解释观察到的运动障碍和进行性僵硬，而不是 DAT 的改变。
