A postsynaptic GPR158-PLCXD2 complex controls spine apparatus abundance and dendritic spine maturation

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• The spine apparatus (SA) is an endoplasmic reticulum (ER)-related organelle in dendritic spines, vital for postsynaptic development.
• SA's role in neurological disorders is known, but its precise localization mechanisms at synapses are unclear.

Purpose of the Study:

• To identify the molecular mechanisms controlling spine apparatus (SA) localization at specific synapses.
• To elucidate the role of a novel signaling complex in SA abundance and dendritic spine maturation.

Main Methods:

• Utilized sparse genetic manipulations in mouse cortical neurons in vivo.
• Investigated the interaction between G protein-coupled receptor (GPCR) GPR158 and phospholipase C (PLC) family member PLCXD2.
• Examined the role of extracellular heparan sulfate proteoglycan (HSPG) binding.

Main Results:

• Identified a postsynaptic signaling complex of GPR158 and PLCXD2 that regulates SA abundance.
• Demonstrated that GPR158 absence leads to uncontrolled PLCXD2 activity, impairing SA incorporation and spine maturation.
• Showed that HSPG binding modulates the GPR158-PLCXD2 interaction for spatiotemporal control.

Conclusions:

• Uncovered a direct GPCR-like receptor-to-PLC signaling pathway independent of G proteins.
• Established the GPR158-PLCXD2 module as a key regulator of SA abundance.
• Highlighted the importance of this pathway for postsynaptic structure, function, and potential therapeutic targets in neurological disorders.