Are dopamine receptor and transporter changes in Rett syndrome reflected in Mecp2-deficient mice?

Dean F Wong; Mary E Blue; James R Brašić; Ayon Nandi; Heather Valentine; Kirstie H Stansfield; Olivier Rousset; Genila Bibat; Mary E Yablonski; Michael V Johnston; Albert Gjedde; SakkuBai Naidu

doi:10.1016/j.expneurol.2018.05.019

Are dopamine receptor and transporter changes in Rett syndrome reflected in Mecp2-deficient mice?

Exp Neurol. 2018 Sep:307:74-81. doi: 10.1016/j.expneurol.2018.05.019. Epub 2018 May 18.

Authors

Affiliations

¹ 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. Electronic address: dfwong@jhu.edu.
² 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. Electronic address: blue@kennedykrieger.org.
³ 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. Electronic address: brasic@jhmi.edu.
⁴ 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. Electronic address: anandi1@jhmi.edu.
⁵ 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. Electronic address: hvalent2@jhmi.edu.
⁶ 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. Electronic address: kirstie.stansfield@gmail.com.
⁷ 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. Electronic address: Olivier@jhu.edu.
⁸ Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, United States. Electronic address: Bibat@kennedykrieger.org.
⁹ Hugo W. Moser Research Institute at Kennedy Krieger, Inc., Baltimore, MD 21205, United States. Electronic address: mcyablon@verizon.net.
¹⁰ 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. Electronic address: Johnston@kennedkrieger.org.
¹¹ 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; Departments of Clinical Research and Nuclear Medicine, Odense University Hospital, University of Southern Denmark, 5000 Odense, Denmark. Electronic address: albert.gjedde@rsyd.dk.
¹² 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. Electronic address: naidu@kennedykrieger.org.

PMID: 29782864
DOI: 10.1016/j.expneurol.2018.05.019

Abstract

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 D₂ receptors (D₂R) and transporters (DAT) in women with RTT and in Mecp2-deficient mice, and D₁R and D₂R density was measured in postmortem human tissue by autoradiography. Results showed 1) significantly reduced D₂R density in the striatum of women with RTT compared to control subjects. 2) PET imaging of mouse striatum similarly demonstrated significant reductions in D₂R density of 7-10 week-old hemizygous (Mecp2-null) and heterozygous (HET) mice compared to wild type (WT) mice. With age, the density of D₂R declined in WT mice but not HET mice. 3) In contrast, postmortem autoradiography revealed no group differences in the density of D₁R and D₂R 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 D₂R more likely explain the impaired ambulation and progressive rigidity observed rather than alterations in DAT.

Keywords: Autoradiography; Binding potential; Gene mutation; Intellectual disability; Neurotransmitter; Nigrostriatal pathway; Partial volume correction; Positron emission tomography; Postmortem; Radioligand.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Child
Child, Preschool
Corpus Striatum / diagnostic imaging
Corpus Striatum / metabolism
Dopamine Plasma Membrane Transport Proteins / biosynthesis*
Female
Humans
Methyl-CpG-Binding Protein 2 / deficiency*
Mice
Mice, Knockout
Receptors, Dopamine D2 / biosynthesis*
Rett Syndrome / diagnostic imaging*
Rett Syndrome / metabolism*
Young Adult

Substances

DRD2 protein, mouse
Dopamine Plasma Membrane Transport Proteins
Mecp2 protein, mouse
Methyl-CpG-Binding Protein 2
Receptors, Dopamine D2

Abstract

Publication types

MeSH terms

Substances

Grants and funding