Scalable amperometric microchip array for high-throughput screening of small molecules, peptides or genetic perturbations for modulation of quantal transmitter release

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` The goal of this project is the development of a scalable n x m electrochemical detector array platform with on- chip amplifiers for massively parallel recordings of quantal transmitter release events. The neurobiological process that this assay analyzes is the process of exocytosis and transmitter release. Neurotransmitters and hormones are stored at high concentration in membrane-bound organelles. Upon stimulation, the contents of these vesicles are released in quantal events through a fusion pore that connects the vesicular lumen to the extracellular space. In the treatment of Parkinson's disease the drug levodopa increases dopamine release from the reduced number of dopaminergic neurons. On the other hand, BoTox treatment acts by reducing transmitter release. In addition to these examples, many other drugs and many molecular manipulations modulate transmitter release in various ways. This regulation of transmitter release occurs not only via changing the number or frequency of quantal release events but also via modulation of quantal size and of the kinetics of release from individual vesicles. The technology developed in this project is adapted from the semiconductor industry and involves a CMOS microelectronic chip for on-chip recordings of single quantal release events of oxidizable transmitter molecules such as noradrenaline, dopamine, or serotonin. The technology will allow the simultaneous recording of single vesicle release events from hundreds of cells without the need for microscopic observation and manipulation, and thereby provides a high-throughput platform to characterize molecular and pharmacological manipulations. This technology will be a very important tool for preclinical drug development studies, including pharmacology, efficacy and toxicology and provide a pipeline for target identification and drug discovery. It will also considerably accelerate research towards understanding vesicular release mechanisms and their modulation by drugs and genetic factors.