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Updated: Dec 20, 2025
Brain Membrane Fractionation: An Ex Vivo Approach to Assess Subsynaptic Protein Localization
Published on: May 12, 2017
A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding
Tao Li1,2, Brian Chiou1, Casey K Gilman2
1Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA.
Abstract:
Developmental synaptic remodeling is important for the formation of precise neural circuitry, and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes, remains elusive. Adhesion G protein-coupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: In neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on presynaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion of Gpr56 leads to increased synapses as a result of reduced microglial engulfment of PS+ presynaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.
Insights
Microglia use the G protein-coupled receptor GPR56 to prune synapses during brain development. This receptor binds phosphatidylserine on presynaptic inputs, ensuring proper synaptic numbers and neural circuit formation.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Synaptic remodeling is crucial for neural circuit formation, and its disruption is linked to neurodevelopmental disorders.
- Microglia's role in synapse pruning is essential but not fully integrated with other developmental processes.
Purpose of the Study:
- To elucidate the mechanism of microglial synapse pruning mediated by the adhesion G protein-coupled receptor GPR56.
- To investigate the role of GPR56 in maintaining synaptic numbers during brain development.
Main Methods:
- Investigated GPR56's function in microglia using genetic deletion models.
- Examined the binding of phosphatidylserine (PS) to GPR56.
- Analyzed synaptic numbers and microglial engulfment of PS+ presynaptic inputs.
Main Results:
- Microglial GPR56 maintains appropriate synaptic numbers in a time- and circuit-dependent manner.
- GPR56 specifically binds phosphatidylserine on presynaptic elements.
- Deletion of Gpr56 in microglia increases synapse numbers due to reduced engulfment of PS+ inputs.
- A specific GPR56 isoform is essential for microglial synapse pruning.
Conclusions:
- Microglial GPR56 acts as a receptor for phosphatidylserine on presynaptic inputs, mediating synapse pruning.
- This mechanism is critical for regulating synaptic numbers during neurodevelopment.
- Isoform-specific GPR56 function provides a molecular basis for microglial synapse elimination.
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