Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities.
Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.
Samaco
Rodney C
RC
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Mandel-Brehm
Caleigh
C
Chao
Hsiao-Tuan
HT
Ward
Christopher S
CS
Fyffe-Maricich
Sharyl L
SL
Ren
Jun
J
Hyland
Keith
K
Thaller
Christina
C
Maricich
Stephen M
SM
Humphreys
Peter
P
Greer
John J
JJ
Percy
Alan
A
Glaze
Daniel G
DG
Zoghbi
Huda Y
HY
Neul
Jeffrey L
JL
D000588:Amines / Q000378:metabolism*; D000818:Animals; D006719:Homovanillic Acid / Q000378:metabolism*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism*; D001523:Mental Disorders / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010641:Phenotype; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000588:Amines; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D006897:Hydroxyindoleacetic Acid; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; D006719:Homovanillic Acid