Molecular regulation of dopamine secretion

Dissecting the regulation of dopamine release using state-of-the-art approaches.

Transmission of chemical signals from one neuron to another, or from a neuron to another type of cell, is the fundamental basis of inter-cellular communication by the nervous system and is performed by secreted neurotransmitters. Of all neurotransmitters, dopamine is the most heavily implicated in human diseases, most notably Parkinson’s disease, schizophrenia and addiction. Dopamine modulates neuronal activity and thus controls the transmission of signals through neural circuits responsible for important behaviours, including voluntary movement, associative learning and motivation. The classical model of neurotransmission involves the release of neurotransmitter at synapses that contain presynaptic and postsynaptic structural elements. Transmission occurs rapidly and with very limited spread of the secreted chemical signal.

Neurotransmission by dopamine is substantially different from this classical model. It is much slower and the signal occurs over a much larger area due to diffusion through the extracellular space. Dopamine-secreting structures, called varicosities, are functionally distinct from the classical model of presynaptic function (Daniel et al. 2009). However, the molecular differences that underpin differences between neurotransmission by dopamine and classical transmitter systems are still largely unknown. Our overall aim is to define the molecular mechanisms that determine dopamine release, linking the machinery of dopamine release to neural function, which will lead to a better understanding of dopamine-dependent behaviours, dopamine-related diseases, and potentially the identification of new molecular targets for therapies.

Classical methods of detecting dopamine have relatively low spatial resolution, which precludes studying dopamine release at the level of single varicosities. We have therefore collaboratively developed a high-resolution nanosensor-based optical method of detecting dopamine release from varicosities (Dinarvand et al. 2020). The nanosensors, based on single-walled carbon nanotubes (SWCNTs), are selective, sensitive and highly photostable. We use this method in combination with genetically modified mice, proteomics, immunocytochemistry, virally-mediated gene delivery, biochemistry and electrophysiology to explore the dopaminergic system.

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