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Microglial MERTK eliminates phosphatidylserine-displaying inhibitory post-synapses
Jungjoo Park1, Yeeun Choi1, Eunji Jung1
1Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
Abstract:
Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite the important roles of this process in development and neurological disorders, the identity and regulation of the "eat-me" signal that initiates glia-mediated phagocytosis of synapses has remained incompletely understood. Here, we generated conditional knockout mice with neuronal-specific deletion of the flippase chaperone Cdc50a, to induce stable exposure of phosphatidylserine, a well-known "eat-me" signal for apoptotic cells, on the neuronal outer membrane. Surprisingly, acute Cdc50a deletion in mature neurons causes preferential phosphatidylserine exposure in neuronal somas and specific loss of inhibitory post-synapses without effects on other synapses, resulting in abnormal excitability and seizures. Ablation of microglia or the deletion of microglial phagocytic receptor Mertk prevents the loss of inhibitory post-synapses and the seizure phenotype, indicating that microglial phagocytosis is responsible for inhibitory post-synapse elimination. Moreover, we found that phosphatidylserine is used for microglia-mediated pruning of inhibitory post-synapses in normal brains, suggesting that phosphatidylserine serves as a general "eat-me" signal for inhibitory post-synapse elimination.
Insights
Microglia eliminate inhibitory synapses using phosphatidylserine as an "eat-me" signal. This process, when dysregulated by Cdc50a deletion, causes seizures, highlighting its role in brain health.
Area of Science:
- Neuroscience
- Cell Biology
- Synaptic Plasticity
Background:
- Glia-mediated phagocytosis is crucial for synapse elimination in the central nervous system.
- The specific signals initiating glia-mediated synapse removal are not fully understood.
- Phosphatidylserine is a known "eat-me" signal for apoptotic cells.
Purpose of the Study:
- To investigate the role of phosphatidylserine as an "eat-me" signal in glia-mediated synapse elimination.
- To understand the regulation of phosphatidylserine exposure on neurons.
- To determine the consequences of aberrant synapse elimination on neuronal function.
Main Methods:
- Generated conditional knockout mice with neuronal-specific deletion of Cdc50a.
- Induced stable phosphatidylserine exposure on neuronal outer membranes.
- Utilized microscopy and electrophysiology to assess synapse loss and neuronal excitability.
- Investigated the role of microglia and Mertk in the observed phenotype.
Main Results:
- Neuronal-specific Cdc50a deletion led to phosphatidylserine exposure on neuronal somas.
- This resulted in preferential loss of inhibitory post-synapses, causing abnormal excitability and seizures.
- Microglia-mediated phagocytosis, via Mertk, was responsible for the elimination of inhibitory post-synapses.
- Phosphatidylserine was identified as a key "eat-me" signal for microglia-mediated pruning of inhibitory synapses in normal brains.
Conclusions:
- Phosphatidylserine acts as a general "eat-me" signal for microglia-mediated elimination of inhibitory post-synapses.
- Dysregulation of this pathway contributes to neurological dysfunction, such as seizures.
- This study elucidates a critical mechanism in synaptic pruning and its implications for brain disorders.
