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Synthesis of Two-Photon Optimized 'Caged' Compounds for Neuroscienes (LIGHTLAB-TOOLS)
Start date: Nov 1, 2014, End date: Oct 31, 2016 PROJECT  FINISHED 

"Progress in science requires the development of new or better experimental tools. Photolysis has provided a way to study kinetics of ligand activated signaling in situ at inaccessible intracellular and extracellular receptors for three decades. It can now be combined with laser microscopy to provide high resolution spatio-temporal kinetics of receptors in situ, for photo-stimulation or photo-inhibition to study dendritic integration and networks, or for studying compartmentalization and distribution of receptors. The main obstacles to its improved application in neuroscience are the poor depth of penetration in neural tissue, a few tens of microns with one-photon excitation, and the requirement for better photolysis efficiency. Two-photon photolysis has inherently better resolution deep in tissues but needs much more efficient photolysis to permit brief exposures at low concentrations without phototoxicity.We plan to develop new caged neuroactive amino acids based on Laport symmetry-allowed aminoquinoline constructs with large two-photon cross-sections, high water solubility and minimal pharmacological interference. Preliminary results showed greater efficiencies than existing cages in photochemical studies and fast activation of synaptic glutamate receptors. The synthesis has been rationally simplified by applying novel methods, and the ligand addition forms a last step, allowing considerable flexibility in the range of neuroactive ligands that can be readily functionalized. The optimized molecular tools will be used to investigate glutamate receptor properties in situ in cerebellar Purkinje neurons and the interaction between fast and metabotropic glutamate receptors at the same synapses. Furthermore caged inhibitory amino acids GABA and glycine will be prepared and used to study the effects of photo-inhibition of individual cells, singly and with multi-spot illumination, on network activity."

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