Widespread changes in dendritic and axonal morphology in Mecp2-mutant mouse models of Rett syndrome: evidence for disruption of neuronal networks.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked gene MECP2. Girls with RTT show dramatic changes in brain function, but relatively few studies have explored the structure of neural circuits. Examining two mouse models of RTT (Mecp2B and Mecp2J), we previously documented changes in brain anatomy. Herein, we use confocal microscopy to study the effects of MeCP2 deficiency on the morphology of dendrites and axons in the fascia dentata (FD), CA1 area of hippocampus, and motor cortex following Lucifer yellow microinjection or carbocyanine dye tracing. At 3 weeks of age, most (33 of 41) morphological parameters were significantly altered in Mecp2B mice; fewer (23 of 39) were abnormal in Mecp2J mice. There were striking changes in the density and size of the dendritic spines and density and orientation of axons. In Mecp2B mice, dendritic spine density was decreased in the FD (approximately 11%), CA1 (14-22%), and motor cortex (approximately 16%). A decreased spine head size (approximately 9%) and an increased spine neck length (approximately 12%) were found in Mecp2B FD. In addition, axons in the motor cortex were disorganized. In Mecp2J mice, spine density was significantly decreased in CA1 (14-26%). In both models, dendritic swelling and elongated spine necks were seen in all areas studied. Marked variation in the type and extent of changes was noted in dendrites of adjacent neurons. Electron microscopy confirmed abnormalities in dendrites and axons and showed abnormal mitochondria. Our findings document widespread abnormalities of dendrites and axons that recapitulate those seen in RTT.
Belichenko
Pavel V
PV
Neuroscience Institute at Stanford University, Stanford, CA 94305-5489, USA. pavel_belichenko@yahoo.com
Wright
Elena E
EE
Belichenko
Nadia P
NP
Masliah
Eliezer
E
Li
Hong Hua
HH
Mobley
William C
WC
Francke
Uta
U
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000648:ultrastructure*; D002232:Carbocyanines; D049229:Dendritic Spines / Q000648:ultrastructure; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology*; D007546:Isoquinolines; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009044:Motor Cortex / Q000473:pathology*; D009474:Neurons / Q000648:ultrastructure*; D015518:Rett Syndrome / Q000235:genetics / Q000473:pathology*
D002232:Carbocyanines; D007546:Isoquinolines; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; C072024:carbocyanine dye DiIC12(3); C017475:lucifer yellow