Identifying the regulation of striatal dopamine function by striatal astrocytes in health and parkinsonism

The neurotransmitter dopamine, in the brain region called the striatum, is vitally important for our everyday actions and motivations. Without dopamine we develop Parkinson's disease and cannot move, but with too much dopamine, we develop addictions. If we could understand more about how dopamine is controlled by the brain, we might better understand how the brain regulates these behaviours, and how we might treat them better in disease.

This project builds on a newly emerging area of neuroscience research that is transforming our understanding of the way brain circuits are regulated. In particular, new research suggests that neurons in the brain can be controlled by non-neuronal cells called astrocytes. In this project, we will explore whether astrocytes might control dopamine function. This is an area of biology which has been completely overlooked until now.

Astrocytes vastly outnumber neurons in the brain and have long been known to be important for generally maintaining the brain and its supply of nutrients. Our current understanding of astrocyte function in brain circuits lags significantly behind our understanding of neuronal function but is now beginning to grow rapidly thanks to the advent of new experimental tools to modulate astrocyte activity. Recent work with these new tools demonstrates that astrocytes have more roles than once believed, and that strikingly, they can play powerful roles in directly regulating neurotransmitter release. In this project, we will examine for the first time, the fundamentally important questions of whether astrocytes in the striatum can modulate dopamine release and function.

Until now, no-one has established whether or not astrocytes play a role in regulating dopamine release in the striatum. We have some new data which strongly suggest that astrocytes play an important role. Our first main aims will be to establish whether astrocytes in striatum dynamically modulate dopamine release, the mechanisms through which they might do it, and whether this impacts on dopamine-dependent behaviours. We will use state-of-the art tools, called chemogenetics and optogenetics, to specifically modulate the activity of astrocytes in mouse brains to understand their impact on dopamine function.

Our second main aim will be to understand better whether there are changes to the biology of astrocytes in the striatum in Parkinson's disease. Astrocytes have been implicated as playing a role in Parkinson's disease, as well as in other neurodegenerative diseases, in which they can lose their supportive roles and gain neurotoxic properties. We have some new data which suggest that there are changes to the way that astrocytes work in striatum in Parkinson's disease and that might have negative consequences for dopamine function in the striatum. In this project, we will develop a better understanding of how astrocytes change in humans as well as in animal models, and test whether and how this impacts negatively on dopamine function in Parkinson's disease.

Overall we expect this new and original project to greatly increase fundamental knowledge about how astrocytes control brain function in health and disease. It should cause a big shift in thinking. We expect to find that astrocytes are key players in governing dopamine function and that there are disruptions to the way that astrocytes operate and control dopamine function in Parkinson's disease. This work could also open up potential new avenues for drug discovery, by identifying disruptions to astrocyte biology that could be targets for future treatments for Parkinson's disease and other dopamine-related disorders.

Emerging evidence indicates that brain astrocytes not only regulate ion balance and blood flow, but also regulate activity of synapses and neural circuits. Astrocytes express receptors and transporters for many transmitters, and consequently, they respond to neurotransmitter input, regulate transmitter levels and release gliotransmitters. Through these mechanisms, astrocytes can act as an extension of neural circuits to regulate neuronal output. With the emergence of new molecular tools to modulate and image astrocyte activity, previously neglected questions about astrocyte-neuron interactions can excitingly now be addressed for the first time.

The neurotransmitter dopamine (DA) is critical to the selection and learning of motivated behaviours, and is dysregulated in disorders spanning Parkinson's disease (PD) to addictions. The fundamental questions of whether astrocyte activity regulates the dynamic release and function of striatal DA, and whether there are changes to astrocyte biology in PD that impact on DA function, have not previously been investigated. We have obtained key pieces of data which support the hypotheses that (1) striatal astrocytes support DA release and (2) this interaction becomes maladaptive in PD. In this timely project, we will exploit new molecular tools that permit targeted manipulation of astrocyte activity to test these hypotheses fully. We will identify: whether and how striatal astrocytes govern DA output on a sub-second timescale; mechanisms and mediators (with a focus on GABA transporters and purinergic gliotransmitters); impact on DA-dependent behaviours; and dysregulation in mouse models and human PD. The findings of this project could radically revise current understanding of the mechanisms that regulate dopamine function, and contribute to a paradigm shift from current neuron-centric views of the mechanisms that gate neural circuits. This work could also provide candidate targets for new treatments for dopaminergic disease.