Learning is a key feature of brain function. The foundation of learning lies in synaptic plasticity, which is the ability of synaptic connections between nerve cells to change in strength and which involve the action of three amino acid neurotransmitters: glycine, glutamate and D-serine. However, certain mechanisms of neurotransmitter signaling remain poorly understood; for instance, which cell types are responsible for regulating D-serine and glycine availability and how does neuronal activity modulate the spatial and temporal distribution of glycine and D-serine in and around the synapse? To investigate these processes, we plan to generate a suite of Designer Optical neuroTransmitter Sensors (DOTS) that can quantitatively and non-invasively visualize small molecules in collaboration with Assistant Professor Harald Janovjak at the Institute of Science and Technology in Vienna, Austria, and Assistant Professor Christian Henneberger at University College, London. This will be achieved by using a combination of structural biology, protein engineering and phylogenetics to ‘resurrect’ ancient amino acid binding proteins, study their interactions with amino acids and tailor their binding and biophycial properties for use as designer optical sensors.