Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression
Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here...
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eLife Sciences Publications Ltd
2016-07-01
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| Online Access: | https://elifesciences.org/articles/15224 |
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doaj-cfbe4addb0a54107a8ffbafde36733672021-05-05T00:30:11ZengeLife Sciences Publications LtdeLife2050-084X2016-07-01510.7554/eLife.15224Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expressionDorothy P Schafer0https://orcid.org/0000-0003-2201-6276Christopher T Heller1Georgia Gunner2Molly Heller3Christopher Gordon4Timothy Hammond5Yochai Wolf6Steffen Jung7Beth Stevens8FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States; Department of Neurobiology, University of Massachusetts Medical School, Worcester, United StatesFM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States; Department of Neurobiology, University of Massachusetts Medical School, Worcester, United StatesFM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States; Department of Neurobiology, University of Massachusetts Medical School, Worcester, United StatesFM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United StatesFM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United StatesFM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United StatesDepartment of Immunology, The Weizmann Institute of Science, Rehovot, IsraelDepartment of Immunology, The Weizmann Institute of Science, Rehovot, IsraelFM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, United StatesMicroglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2tm1.1Bird/y). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1CreER;Mecp2fl/yor Cx3cr1CreER; Mecp2LSL/y) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types.https://elifesciences.org/articles/15224microgliaRett SyndromeMecp2synapseengulfment |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Dorothy P Schafer Christopher T Heller Georgia Gunner Molly Heller Christopher Gordon Timothy Hammond Yochai Wolf Steffen Jung Beth Stevens |
| spellingShingle |
Dorothy P Schafer Christopher T Heller Georgia Gunner Molly Heller Christopher Gordon Timothy Hammond Yochai Wolf Steffen Jung Beth Stevens Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression eLife microglia Rett Syndrome Mecp2 synapse engulfment |
| author_facet |
Dorothy P Schafer Christopher T Heller Georgia Gunner Molly Heller Christopher Gordon Timothy Hammond Yochai Wolf Steffen Jung Beth Stevens |
| author_sort |
Dorothy P Schafer |
| title |
Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression |
| title_short |
Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression |
| title_full |
Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression |
| title_fullStr |
Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression |
| title_full_unstemmed |
Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression |
| title_sort |
microglia contribute to circuit defects in mecp2 null mice independent of microglia-specific loss of mecp2 expression |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2016-07-01 |
| description |
Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2tm1.1Bird/y). We demonstrate that microglia contribute to pathogenesis by excessively engulfing, thereby eliminating, presynaptic inputs at end stages of disease (≥P56 Mecp2 null mice) concomitant with synapse loss. Furthermore, loss or gain of Mecp2 expression specifically in microglia (Cx3cr1CreER;Mecp2fl/yor Cx3cr1CreER; Mecp2LSL/y) had little effect on excessive engulfment, synapse loss, or phenotypic abnormalities. Taken together, our data suggest that microglia contribute to end stages of disease by dismantling neural circuits rendered vulnerable by loss of Mecp2 in other CNS cell types. |
| topic |
microglia Rett Syndrome Mecp2 synapse engulfment |
| url |
https://elifesciences.org/articles/15224 |
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1721476310733160448 |