Role of cell-surface receptor signaling mechanisms in dendritic spine maturation and plasticity

Synapses, the highly organized cellular junctions between pre-and postsynaptic neurons, are essential for information transfer and processing in the nervous system. While we have made considerable progress in identifying the cell-surface receptors that are important for the organization and maturation of synapses, the downstream signalling mechanisms remain essentially unknown. Elucidating these intracellular signal transduction pathways is important to better understand how synapses form and change in response to neural activity, and how these processes may be perturbed in neurodevelopmental disorders. We recently identified a novel mechanism by which one synaptic organizing cell-surface receptor, the postsynaptic G protein-coupled receptor-like protein Gpr158, regulates the maturation of dendritic spines in cortical and hippocampal neurons. Our findings suggest that Gpr158-mediated cell-surface to endoplasmic reticulum (ER) communication is an important regulator of dendritic spine maturation. In this project, we will elucidate the signalling mechanisms downstream of Gpr158 and determine whether these also play a role in synaptic plasticity-induced changes in dendritic spines. We will characterize the protein composition of ER – cell-surface contacts in cultured neurons and in vivo using proteomics screening approaches and determine how protein composition may change in response to neural activity. Finally, we will determine whether the identified molecular mechanisms are broadly applicable to other synaptic cell-surface receptors in the control of dendritic spine maturation and plasticity. The results will provide key insight into the intracellular signalling mechanisms that control dendritic spine maturation and plasticity.