Protein Interaction Regulates Synapse Maturation in the Brain

A research team led by Joris De Wit from VIB-KU Leuven has uncovered how two proteins, GPR158 and PLCXD2, work together to control the development of synaptic connections in the brain. Their findings, published in Developmental Cell, shed light on the formation of the spine apparatus, an organelle crucial for stabilizing mature synapses and supporting learning and memory.

Synapses, the points where neurons communicate, contain specialized structures that fine-tune their function. The spine apparatus acts as a calcium reservoir, which is essential for the maturation of dendritic spines—small protrusions on neurons that receive signals. However, the mechanisms controlling the formation of this organelle were previously unclear.

The study identified a new protein complex at synapses, showing that GPR158 interacts with PLCXD2, an enzyme not previously known to function in the brain. PLCXD2 was found to negatively regulate the formation of the spine apparatus by altering the lipid environment within dendritic spines, disrupting assembly sites. GPR158 counteracts this effect by binding to and inhibiting PLCXD2, thereby promoting proper spine apparatus formation.

In neurons lacking GPR158, PLCXD2 activity was unrestrained, resulting in fewer spine apparatus structures and a shift toward immature synaptic features. These changes were associated with reduced levels of neurotransmitter receptors, which are vital for effective neuronal communication. When PLCXD2 was removed in these neurons, the abundance of the spine apparatus and the maturation of dendritic spines were restored.

Ben Verpoort, the study’s first author, noted, “We see underdeveloped synapses that likely communicate less effectively, which could have severe consequences for learning and memory formation.”

“Understanding how this molecular brake works gives us a new handle on synaptic development and plasticity,” says Prof. de Wit. “It opens exciting avenues for studying how synapses stabilize, or fail to, in disorders of brain connectivity.”