Article

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

Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.
Nature (impact factor: 36.28). 03/2012; 484(7392):105-9. DOI:10.1038/nature10907 pp.105-9
Source: PubMed

ABSTRACT Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.

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Keywords

body weight
 
brain parenchyma
 
breathing patterns
 
data implicate microglia
 
devastating disorder
 
disease pathology
 
feasible therapeutic approach
 
irradiation-conditioned Mecp2-null hosts
 
MECP2 gene
 
microglial engraftment
 
microglial phenotype
 
primary neuronal dysfunction
 
Rett pathophysiology
 
significant improvements
 
tissue-resident phagocytes
 
wild-type bone marrow
 
wild-type Mecp2-expressing microglia
 
wild-type microglia
 
wild-type microglial engraftment
 
X-linked autism spectrum disorder