Synapses – the communication points between neurons – are not only molecularly diverse but also contain specialized organelles, tiny internal cellular machines, that finetune their function. The spine apparatus is one such organelle, and it is essential for stabilizing mature synapses and supporting learning and memory. Yet, how neurons control where and when this organelle forms have remained open questions. Researchers from the lab led by Prof. Joris De Wit have discovered an important clue to how connections between brain cells mature. These new findings, published in Developmental Cell, demonstrated how two different proteins, GPR158 and PLCXD2, interact to form a specific component in developing synapses – the spine apparatus.
GPR158 is a probable glycione metabotropic receptor expressed in the brain and possible involved in mood regulation, since post-mortem brains of subjects with major depression this receptor showed a remarkable up-regulation. In the brain prefrontal cortex of rats, moreover, it has been shown to regulate stress-induced depressive onset. PLCXD2, instead, catalyzes the hydrolysis of inositol from phosphatidylinositol (PI). Could also hydrolyze various multi-phospho-inositides, such as phosphatidylinositol-4,5 bisphosphate (PIP2), releasing inositol-1,4,5-trisphosphate (IP3) and the protein kinase C activator diacylglycerol (DAG), therefore mediating cell signaling. Beside PLCXD2, GPR158 associates with RGS7, a universal protein G signaling controller.
Now, the research team has identified a novel synaptic protein complex that regulates the incorporation of the spine apparatus in developing synapses. Their study reveals that the receptor GPR158 interacts with an atypical enzyme, PLCXD2, to control spine apparatus abundance and the maturation of dendritic spines – the tiny protrusions on neurons that receive synaptic input. Using a combination of molecular biology and advanced imaging techniques, the team identified PLCXD2 as a negative regulator of spine apparatus formation. PLCXD2 alters the local lipid environment within dendritic spines, disrupting key sites necessary for spine apparatus assembly. Further experiments revealed that GPR158 operates by directly binding to and inhibiting PLCXD2.
This interaction neutralizes PLCXD2’s suppressive effect, lifting the brake on spine apparatus formation, allowing it to assemble properly. In neurons lacking GPR158, unchecked PLCXD2 activity led to a marked reduction in spine apparatus abundance accompanied by a shift toward immature synaptic structures. These immature dendritic spines fail to fully sustain synaptic communication, a finding supported by experiments showing reduced levels of essential neurotransmitter receptors – proteins critical for relaying signals between neurons. Remarkably, removing PLCXD2 in these same neurons restored spine apparatus abundance and normalized dendritic spine maturation, directly linking the maturation defect to the unopposed activity of PLCXD2.
Understanding how the spine apparatus forms and functions is especially important because it has been implicated in brain disorders like Alzheimer’s and depression, where calcium imbalance and impaired synaptic signaling are key features. This newly identified GPR158–PLCXD2 axis offers insight into how synaptic structure and receptor content are regulated during brain development, and what might go wrong in disease, considering that RGS7 has been implcated in widespread conditions like autism.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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