Publication Date:
2011-07-01
Description:
Rett's syndrome (RTT) is an X-chromosome-linked autism spectrum disorder caused by loss of function of the transcription factor methyl-CpG-binding protein 2 (MeCP2). Although MeCP2 is expressed in most tissues, loss of MeCP2 expression results primarily in neurological symptoms. Earlier studies suggested the idea that RTT is due exclusively to loss of MeCP2 function in neurons. Although defective neurons clearly underlie the aberrant behaviours, we and others showed recently that the loss of MECP2 from glia negatively influences neurons in a non-cell-autonomous fashion. Here we show that in globally MeCP2-deficient mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern, and greatly prolonged lifespan compared to globally null mice. Furthermore, restoration of MeCP2 in the mutant astrocytes exerted a non-cell-autonomous positive effect on mutant neurons in vivo, restoring normal dendritic morphology and increasing levels of the excitatory glutamate transporter VGLUT1. Our study shows that glia, like neurons, are integral components of the neuropathology of RTT, and supports the targeting of glia as a strategy for improving the associated symptoms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268776/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268776/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lioy, Daniel T -- Garg, Saurabh K -- Monaghan, Caitlin E -- Raber, Jacob -- Foust, Kevin D -- Kaspar, Brian K -- Hirrlinger, Petra G -- Kirchhoff, Frank -- Bissonnette, John M -- Ballas, Nurit -- Mandel, Gail -- P30 NS061800/NS/NINDS NIH HHS/ -- R01 HD056503/HD/NICHD NIH HHS/ -- R01 HD056503-03/HD/NICHD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 29;475(7357):497-500. doi: 10.1038/nature10214.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21716289" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anxiety/metabolism
;
Astrocytes/metabolism
;
Behavior, Animal
;
Disease Progression
;
Female
;
Gene Expression Regulation
;
Male
;
Methyl-CpG-Binding Protein 2/deficiency/genetics/metabolism
;
Mice
;
Mice, Inbred C57BL
;
Motor Activity
;
Neuroglia/*metabolism/pathology
;
Neurons/metabolism
;
Rett Syndrome/*genetics/*metabolism/physiopathology
;
Vesicular Glutamate Transport Protein 1/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
