Microglial MERTK eliminates phosphatidylserine-displaying inhibitory post-synapses

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.