Faculty Opinions recommendation of Wild-type microglia arrest pathology in a mouse model of Rett syndrome.

2012 ◽  
Author(s):  
X William Yang ◽  
Anthony Daggett
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Wild Type

scholarly journals Astrocytic modulation of excitatory synaptic signaling in a mouse model of Rett syndrome

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Benjamin Rakela ◽  
Paul Brehm ◽  
Gail Mandel
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Synaptic Activity ◽  
Wild Type ◽  
Synaptic Signaling ◽  
Network Function ◽  
Mosaic Distribution ◽  
Mutant Cells ◽  
The Brain ◽  
Expression Status

Studies linking mutations in Methyl CpG Binding Protein 2 (MeCP2) to physiological defects in the neurological disease, Rett syndrome, have focused largely upon neuronal dysfunction despite MeCP2 ubiquitous expression. Here we explore roles for astrocytes in neuronal network function using cortical slice recordings. We find that astrocyte stimulation in wild-type mice increases excitatory synaptic activity that is absent in male mice lacking MeCP2 globally. To determine the cellular basis of the defect, we exploit a female mouse model for Rett syndrome that expresses wild-type MeCP2-GFP in a mosaic distribution throughout the brain, allowing us to test all combinations of wild-type and mutant cells. We find that the defect is dependent upon MeCP2 expression status in the astrocytes and not in the neurons. Our findings highlight a new role for astrocytes in regulation of excitatory synaptic signaling and in the neurological defects associated with Rett syndrome.

scholarly journals Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2269 ◽  
Author(s):  
Sampathkumar Rangasamy ◽  
Shannon Olfers ◽  
Brittany Gerald ◽  
Alex Hilbert ◽  
Sean Svejda ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Critical Role ◽  
Mtor Pathway ◽  
Paternal Allele ◽  
Cellular Phenotype ◽  
Wild Type ◽  
Soma Size ◽  
Neuronal Size

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked MECP2 gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (Mecp2 A140V “knock-in” mutant) expressing the recurrent human MECP2 A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN) cultures from mutant (Mecp2A140V/y) and wild type (Mecp2+/y) male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele) and a wild type Mecp2 gene linked to an eGFP transgene (paternal allele). In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V) allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1) treatment of neuronal cells from Mecp2 mutant mice rescued the soma size phenotype. We also found that Mecp2  mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i) reduced neuronal size is an important in vitro cellular phenotype of Mecp2 mutation in mice, and ii) MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput, in vitro assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”).

scholarly journals Wild-type microglia arrest pathology in a mouse model of Rett syndrome

Nature ◽  
2012 ◽  
Vol 484 (7392) ◽  
pp. 105-109 ◽  
Author(s):  
Noël C. Derecki ◽  
James C. Cronk ◽  
Zhenjie Lu ◽  
Eric Xu ◽  
Stephen B. G. Abbott ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Wild Type

scholarly journals Defects in brainstem neurons associated with breathing and motor function in the Mecp2R168X/Y mouse model of Rett syndrome

2016 ◽  
Vol 311 (6) ◽  
pp. C895-C909 ◽  
Author(s):  
Christopher M. Johnson ◽  
Weiwei Zhong ◽  
Ningren Cui ◽  
Yang Wu ◽  
Hao Xing ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Motor Function ◽  
Neurodevelopmental Disorder ◽  
Motor Dysfunction ◽  
Membrane Properties ◽  
Wild Type ◽  
Lower Body Weight ◽  
Associated Functions ◽  
Intrinsic Membrane Properties

Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mostly by disruption of the MECP2 gene. Among several RTT-like mouse models, one of them is a strain of mice that carries an R168X point mutation in Mecp2 and resembles one of the most common RTT-causing mutations in humans. Although several behavioral defects have previously been found in the Mecp2R168X/Y mice, alterations in nerve cells remain unknown. Here we compare several behavioral and cellular outcomes between this Mecp2R168X/Y model and a widely used Mecp2Bird/Y mouse model. With lower body weight and shorter lifespan than their wild-type littermates, the Mecp2R168X/Y mice showed impairments of breathing and motor function. Thus we studied brainstem CO2-chemosensitive neurons and propriosensory cells that are associated with these two functions, respectively. Neurons in the locus coeruleus (LC) of both mutant strains showed defects in their intrinsic membrane properties, including changes in action potential morphology and excessive firing activity. Neurons in the mesencephalic trigeminal nucleus (Me5) of both strains displayed a higher firing response to depolarization than their wild-type littermates, likely attributable to a lower firing threshold. Because the increased excitability in LC and Me5 neurons tends to impact the excitation-inhibition balances in brainstem neuronal networks as well as their associated functions, it is likely that the defects in the intrinsic membrane properties of these brainstem neurons contribute to the breathing abnormalities and motor dysfunction. Furthermore, our results showing comparable phenotypical outcomes of Mecp2R168X/Y mice with Mecp2Bird/Y mice suggest that both strains are valid animal models for RTT research.

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