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An Electrochemiluminescence-Based Assay for MeCP2 Protein Variants
Published on: May 22, 2020
Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression
Dorothy P Schafer1,2, Christopher T Heller1,2, Georgia Gunner1,2
1FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, United States.
Abstract:
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 (Mecp2(tm1.1Bird/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 (Cx3cr1(CreER);Mecp2(fl/y)or Cx3cr1(Cr)(eER); Mecp2(LSL/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.
Insights
Microglia contribute to Rett Syndrome (RTT) end-stage pathology by engulfing neural inputs, worsening synapse loss. Modifying Mecp2 in microglia did not alter this process, indicating they dismantle vulnerable circuits in RTT.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Microglia, the brain's immune cells, are implicated in Rett Syndrome (RTT) pathogenesis.
- The precise role of microglia in RTT remains unclear, with some evidence suggesting they are not causative.
- Rett Syndrome is an X-linked neurodevelopmental disorder affecting brain development and function.
Purpose of the Study:
- To investigate the role of microglia in the pathogenesis of Rett Syndrome using a mouse model.
- To determine how microglia contribute to disease progression in the Mecp2 null mouse model.
- To assess the impact of Mecp2 expression in microglia on disease phenotypes.
Main Methods:
- Utilized the retinogeniculate system in Mecp2 null mice (Mecp2(tm1.1Bird/y)) to study microglial function.
- Examined presynaptic input engulfment and synapse loss at later disease stages (≥P56).
- Generated conditional knockout/knockin mouse models (Cx3cr1(CreER);Mecp2(fl/y) and Cx3cr1(Cr)(eER); Mecp2(LSL/y)) to manipulate Mecp2 expression specifically in microglia.
Main Results:
- Microglia were found to excessively engulf presynaptic inputs, leading to synapse loss in end-stage Mecp2 null mice.
- Loss or gain of Mecp2 specifically in microglia did not significantly affect excessive engulfment or synapse loss.
- Phenotypic abnormalities in the RTT mouse model were largely independent of Mecp2 status in microglia.
Conclusions:
- Microglia contribute to the end stages of Rett Syndrome pathogenesis by dismantling neural circuits.
- This microglial-mediated dismantling occurs in circuits already vulnerable due to Mecp2 loss in other CNS cell types.
- Microglia's role appears to be exacerbating existing pathology rather than initiating it.
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