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

The spine apparatus (SA), an endoplasmic reticulum (ER)-related organelle present in a subset of dendritic spines, plays a key role in postsynaptic development and is implicated in various neurological disorders. The molecular mechanisms that dictate SA localization at selected synapses remain elusive. Here, we identify a postsynaptic signaling complex comprising the G protein-coupled receptor (GPCR)- GPR158 and a constitutively active phospholipase C (PLC) family member, PLC X-domain containing 2 (PLCXD2), that controls SA abundance. Sparse genetic manipulations of mouse cortical neurons in vivo demonstrate that, in the absence of GPR158, unrestrained PLCXD2 activity impedes postsynaptic SA incorporation and hampers structural and functional dendritic spine maturation. Extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction, providing spatiotemporal control over GPR158 signaling. Together, our findings uncover a direct GPCR-like receptor-to-PLC signaling pathway that bypasses canonical PLC regulation via G proteins. This GPR158-PLCXD2 module regulates SA abundance, essential for proper postsynaptic structure and function.