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

Nature 2012 Mar 18;484(7392):105-9. Epub 2012 Mar 18.

Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.

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.

Download full-text PDF

http://dx.doi.org/10.1038/nature10907DOI Listing
March 2012
Get 20% Off Journals at LWW.com

Similar Publications

Participation and engagement in family activities among girls and young women with Rett syndrome living at home with their parents - a cross-sectional study.

Disabil Rehabil 2021 Feb 23:1-11. Epub 2021 Feb 23.

The ADL Unit, The Parker Institute, Copenhagen University hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.

Purpose: To describe the extent of participation and engagement in family activities and explore variables potentially impacting on these factors in family activities among girls and young women with Rett syndrome (RTT) under the age of 21.

Materials And Methods: The Child Participation in Family Activities (Child-PFA) questionnaire was sent to parents in the target group ( = 42). Additionally, age, number of siblings at home, ambulation level, clinical severity and level of hand function were recorded to explore possible impact. Read More

View Article and Full-Text PDF
February 2021

Autonomic Characteristics of Sudden Unexpected Death in Epilepsy in Children-A Systematic Review of Studies and Their Relevance to the Management of Epilepsy in Rett Syndrome.

Front Neurol 2020 5;11:632510. Epub 2021 Feb 5.

Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

To systematically identify and critically appraise studies that investigate the autonomic characteristics of Sudden Unexpected Death in Epilepsy (SUDEP) in the pediatric population. We also wanted to explore how this information would be relevant to the management of epilepsy in patients with Rett Syndrome. Using PRISMA guidelines, a systematic review of PubMed, Scopus, Cochrane, PsycINFO, Embase, and Web of Science databases was performed to identify eligible studies. Read More

View Article and Full-Text PDF
February 2021

Stimulation of the Serotonin Receptor 7 Restores Brain Histone H3 Acetylation and MeCP2 Corepressor Protein Levels in a Female Mouse Model of Rett Syndrome.

J Neuropathol Exp Neurol 2021 Feb;80(3):265-273

Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Roma, Italy.

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene, characterized by severe behavioral and physiological impairments for which no cure is available. The stimulation of serotonin receptor 7 (5-HT7R) with its selective agonist LP-211 (0.25 mg/kg/day for 7 days) was proved to rescue neurobehavioral alterations in a mouse model of RTT. Read More

View Article and Full-Text PDF
February 2021

DLG4-related synaptopathy: a new rare brain disorder.

Agustí Rodríguez-Palmero Melissa Maria Boerrigter David Gómez-Andrés Kimberly A Aldinger Íñigo Marcos-Alcalde Bernt Popp David B Everman Alysia Kern Lovgren Stephanie Arpin Vahid Bahrambeigi Gea Beunders Anne-Marie Bisgaard V A Bjerregaard Ange-Line Bruel Thomas D Challman Benjamin Cogné Christine Coubes Stella A de Man Anne-Sophie Denommé-Pichon Thomas J Dye Frances Elmslie Lars Feuk Sixto García-Miñaúr Tracy Gertler Elisa Giorgio Nicolas Gruchy Tobias B Haack Chad R Haldeman-Englert Bjørn Ivar Haukanes Juliane Hoyer Anna C E Hurst Bertrand Isidor Maria Johansson Soller Sulagna Kushary Malin Kvarnung Yuval E Landau Kathleen A Leppig Anna Lindstrand Lotte Kleinendorst Alex MacKenzie Giorgia Mandrile Bryce A Mendelsohn Setareh Moghadasi Jenny E Morton Sebastien Moutton Amelie J Müller Melanie O'Leary Marta Pacio-Míguez Maria Palomares-Bralo Sumit Parikh Rolph Pfundt Ben Pode-Shakked Anita Rauch Elena Repnikova Anya Revah-Politi Meredith J Ross Claudia A L Ruivenkamp Elisabeth Sarrazin Juliann M Savatt Agatha Schlüter Bitten Schönewolf-Greulich Zohra Shad Charles Shaw-Smith Joseph T Shieh Motti Shohat Stephanie Spranger Heidi Thiese Frederic Tran Mau-Them Bregje van Bon Ineke van de Burgt Ingrid M B H van de Laar Esmée van Drie Mieke M van Haelst Conny M van Ravenswaaij-Arts Edgard Verdura Antonio Vitobello Stephan Waldmüller Sharon Whiting Christiane Zweier Carlos E Prada Bert B A de Vries William B Dobyns Simone F Reiter Paulino Gómez-Puertas Aurora Pujol Zeynep Tümer

Genet Med 2021 Feb 17. Epub 2021 Feb 17.

Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Purpose: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.

Methods: The clinical and genetic information were collected through GeneMatcher collaboration. Read More

View Article and Full-Text PDF
February 2021

Longitudinal cognitive rehabilitation applied with eye-tracker for patients with Rett Syndrome.

Res Dev Disabil 2021 Feb 10;111:103891. Epub 2021 Feb 10.

Department of Clinical and Experimental Medicine, University of Messina, Via Bivona, 98100, Messina, Italy. Electronic address:

Background: longitudinal effects of cognitive rehabilitation in Rett Syndrome (RTT) have been poorly investigated and the mechanisms do not appear to have been described in detail.

Aims: the aim of this study was to examine the effects of cognitive rehabilitation with eye-tracker technology on attention, choice behaviours and language over a 2-year period in patients with RTT.

Methods And Procedures: 28 participants with RTT, ranging from age 4-22 years old (M = 13. Read More

View Article and Full-Text PDF
February 2021