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Development of flash photolysis for deep uncaging in vivo and high throughput characterisation of neurotransmitter gated ion channels in drug discovery


Flash photolysis is widely applied in cell physiology to initiate neurotransmitter and other ligand'receptor interactions in conditions that are subject to poor diffusional access and receptor desensitisation, and for labile ligands. It has the potential to initiate reactions on physiological time and spatial scales (sub-msec and sub-micron) in complex tissues such as brain slices, and is often combined with electrophysiology and optical imaging. However, this potential is unrealised in neuroscience and medicine in several areas:
- The design of new 'cages? optimised to make use of the localisation achievable with the two photon effect;
- Wavefront modulation of photolysis light to make z axis location and spot size readily changeable
- Its application in high throughput screening for drug discovery of ligands acting at rapidly desensitising neurotransmitter receptors in the brain.

The PHOTOLYSIS consortium comprises neurophysiologists, photochemists, optical physicists, specialists in high throughput patch clamp screening, and ion channel targeted drug discovery, to address these areas. New photochemistry of cages combined with novel pulsed lasers and adaptive optics will together optimise the efficiency, depth and location of photolysis in whole brain in vivo and in vitro.

These developments will be combined with deep imaging (i) to identify mediators and cell types in neurovascular coupling of blood perfusion to neuronal activity (ii) Applied to synaptic transmission to study postsynaptic channels in situ, their role in synaptic plasticities, and (iii) to the interactions between metabotropic receptors and fast transmitter channels. Finally, near UV flash photolysis will be adapted to patch clamp HTS technology to characterise drugs acting at fast activating and desensitising neurotransmitter receptors, to study the functional pharmacology of genetically-linked channelopathies, and in developing therapies with somatic cell replacement.

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Participants (7)