Verkenning van de rol van communicatie tussen het celoppervlak en het ER tijdens de ontwikkeling van synapsen

The brain is a highly heterogeneous tissue, composed of many neuronal cell types that communicate through even more diverse types of synapses. This cell- and synapse-type diversity is critical for the proper function of neural circuits, but poses a major challenge for elucidating the molecular mechanisms regulating the connectivity, plasticity and maintenance of synapses. Recent work from our lab has identified the largely uncharacterized G protein-coupled receptor (GPCR) GPR158 as a key regulator of a specific synaptic connection in the hippocampus: the mossy fiber (MF) synapse, which connects dentate gyrus granule cells with CA3 pyramidal neurons, a major information-processing pathway that undergoes extensive learning-related plasticity throughout life. Our findings show that GPR158 localizes to the postsynaptic side of the MF-CA3 connection and organizes the unique structural and functional features of this synapse. The identification of GPR158 provides a molecular entry point to start dissecting the molecular programs controlling synapse-specific features. Furthermore, the continued expression of GPR158 in adult CA3 neurons and in the somatosensory cortex, two brain regions associated with pronounced structural and functional plasticity, suggests that GPR158 remains an important regulator of synapse-specific structure and function at later stages, for instance in experience-dependent plasticity. We hypothesize that GPR158 controls key synaptic signaling pathways that regulate synapse structure and function important for connectivity and plasticity. Disruption of these pathways will perturb synaptic connectivity and plasticity, and impair circuit function. The aim of this PhD project was to unravel the signaling pathways by which GPR158 regulates synaptic structure and function, using molecular and cellular biology, bioinformatics, mouse genetics, and imaging (light and electron microscopy) approaches. Our findings uncover a novel postsynaptic signaling complex comprising GPR158 and PLCXD2, an unusual phospholipase C family member (PLC) with no known function in the brain. We demonstrate that the GPR158-PLCXD2 complex operates in vivo to regulate postsynaptic spine apparatus (SA) content and the structural and functional maturation of dendritic spines. Finally, we show that heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction and downstream function, providing a possible mechanism to fine-tune SA incorporation in a synapse-specific manner. Given their strong involvement in the etiology of various neurodevelopmental disorders, a better understanding of how synaptic CAMs signal at the synapse is highly relevant and may provide invaluable insight towards the development of therapeutic strategies.