MICA: Role of D1R-D3R heteromers on striatal function in L-DOPA-induced dyskinesias

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Many people with Parkinson's disease do not respond well to therapy with the most widely-used drug called L-DOPA, having uncontrollable body movements that make them feel ashamed or even fall and get injured. We and other doctors think that this occurs because proteins called dopamine receptors associate in unusual structures called heteromers in nerve cells. However, no one knows how and where heteromers are formed, whether they affect other receptors and if it actually makes people feel bad. We have shown that there really are many more heteromers in brains of the animals with experimental Parkinson's disease put on human therapy. Now, we want to use special animals that will enable us to see where heteromers are formed. Further, we made contacts with companies to make smaller proteins of our design that will break heteromers apart, which could then be used to prevent side effects of drugs. A part of the brain that is essential for manifestations of Parkinson's disease is called striatum. It is controlled by inflow of impulses that release a substance called dopamine. The main problem of Parkinson's disease is that the source of dopamine is lost. In therapy, L-DOPA serves to compensate for the lack of dopamine.Importantly, not all nerve cells in striatum are the same: there are two subtypes with contrasting properties, particularly how they react to dopamine. Nerve cells communicate and transmit information across structures called synapses. The sending nerve cell (presynaptic) relays the information by releasing chemical transmitters. The receiving cell (postsynaptic) detects that signal by specialized receptor proteins present on its body or fine extensions called dendrites. At the points of contact, dendrites have bud-like protrusions called dendritic spines that possess molecular machinery necessary to process the signal. Different types of dopamine receptors in striatal spines respond to dopamine differently, transmitting the signal in a specific way. Normally they stand apart, but can also aggregate into heteromers, which will transmit the signal in a different way.Among other specialized receptor proteins in spines are AMPA and NMDA receptors, responsible for nearly all of the fast communication between neurones in the brain.A lot is known about interplay between AMPA, NMDA and dopamine receptors, both in health and Parkinson's disease. For example, we know many ways how they affect each other to work more or less strongly or how the signals from one receptor make other receptors to incorporate into the synapse or completely leave it, thus modulating the overall synaptic function. Almost nothing is, however, known whether the same rules apply when dopamine receptor-heteromers are present, or about the consequences they may have in Parkinson's disease. This is important because it could tell us why patient's brains make wrong calculations and send wrong signals that result in unwanted movements. To answer all these questions, we will use special animals that allow us to tell between subtypes of nerve cells in striatum, even allowing us to see when heteromers are present in them, because they become fluorescent. We will apply chemicals that cause Parkinson's disease-like condition in these animals. Then, using special methods, we will be able to track the fluorescent dopamine receptor heteromers and see them within the living cells. To achieve this, we will use a powerful confocal microscopy to see tiny details within nerve cells. We are good in applying this methodology, so we can minimize the number of animals used. Understanding what heteromers do and how they themselves are regulated will help us try to find the way to prevent them from overtaking control over striatum. This will help us devise a new strategy in fight against Parkinson's disease and the deleterious side effects of its treatment.