The role of post-synaptic GPCR intracellular trafficking and signalling on synaptic plasticity (360G-Wellcome-218650_Z_19_Z)

G protein-coupled receptors (GPCRs) are the largest family of signalling receptors, regulating a variety of cellular functions including neurogenesis and synaptogenesis. Therefore, GPCRs are the main pharmaceutical targets, however, the lack of knowledge regarding the association between neuroplasticity and GPCR function makes them an underexploited target for neurodegeneration. GPCR signalling activity is regulated via their trafficking to intracellular compartments, namely endosomes. Membrane trafficking of neuronal receptors is an established mechanism in the regulation of synaptic plasticity, especially in those areas of the brain involved in learning and memory (e.g. hippocampus), although the molecular mechanisms and its link with signalling remain poorly understood. Using beta-adrenergic receptors (BARs) as prototype GPCRs, we aim to target this knowledge gap by 1) identifying BAR trafficking pathways in hippocampal neurons; 2) generating a map of BAR signalling along their endosomal trafficking; 3) determining the role of BAR spatially encoded signalling on synaptic plasticity. Through the development of novel approaches to study the local organization of synapses, this project will help to understand how GPCR activity can be modulated via targeting receptors to defined cellular locations in the hippocampal neuron and specifically within individual synapses, offering the potential for novel GPCR-based therapeutic targets for neurodegeneration.