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cAMP-dependend plasticity of striatal projection neurons in health and disease

Periodic Reporting for period 1 - SCAMPICITY (cAMP-dependend plasticity of striatal projection neurons in health and disease)

Reporting period: 2019-04-01 to 2021-03-31

Neurons are very complex cells, with complex functions. They build the foundation of how our brains work, and understanding neurons is therefore a necessary step to understand the brain. In this project we focused on a very specific type of neuron, the spiny projection neuron of the striatum. The striatum is an evolutionary conserved area of the brain and part of the basal ganglia, a sub-cortical network that is involved in the control of movement. Many movement disorders, such as Parkinson’s disease, are characterized by dysfunction of the basal ganglia and striatal neurons. Parkinson’s disease is the second most common neurodegenerative disorder and an increasing risk for aging societies. Unfortunately, there is no cure of the disease, and symptomatic treatment (such as with L-DOPA) is not without problems. Since striatal neurons play a major part in the disease pathology, advancing the knowledge about their function harbors the potential of developing new therapeutic approaches.
In specific, this project was aimed at understanding the role of cyclic nucleotides in spiny projection neuron function. Cyclic nucleotides are important second messengers in many nerve cells, and their most prominent members are cyclic adenosine monophosphate and cyclic guanosine monophosphate (cAMP and cGMP, respectively). The first main objective therefore was to investigate how synaptic plasticity of striatal neurons is influenced by cyclic nucleotides, specifically cAMP. Secondly, we wanted to know if this regulation is altered in a model of Parkinson’s disease.
We started investigating how synaptic transmission in striatal neurons is affected by common, pharmacological manipulators of cAMP. To our surprise, we could not establish that there is a major effect by solely stimulating cAMP. However, in control experiments we observed that broad inhibition of phosphodiesterases (i.e. enzymes that degrade cAMP and cGMP) has a dramatic effect on synaptic transmission. We continued to elaborate on this finding and further dissect its mechanisms. The main results of these studies is that striatal synaptic transmission is under tight control of phosphodiesterases, and that it is cGMP, not cAMP, playing the key role in this process. Importantly, we were also able to show that these cGMP-dependent processes are necessary for motor skill learning in mice. Our findings have been compiled into a research paper that is currently under review. We have also presented them at a scientific conference and included data from this study in multiple research grant applications.
Based on this first part, we continued to focus on cGMP-dependent regulation of synaptic process in the striatum, in a model of Parkinson’s disease. Our data so far show, that these processes are heavily altered in the disease model and we are currently investigating the underlying mechanisms. To this end, we have established new collaborations in order to obtain tools and transgenic mouse lines to deeper dissect sources and effectors of cGMP signaling in the striatum. Data from this second part have been used for multiple grant applications, but have not been further disseminated yet.
This project has pushed the current state of the art by using the complementary competences of the fellowship-holder and the supervisor/host institute. The extensive use of novel tools (such as for optogenetic stimulation, imaging and genetic scavengers for cGMP) in striatal neurons has, to the best of our knowledge, not been attempted before. The central outcome of this project is that against all expectations, striatal synapses are heavily controlled by cGMP and not cAMP. This finding diverges from typical textbook knowledge and promises to open new ways of understanding the processes governing synaptic transmission – also on other non-striatal synapses. Lastly, showing that these processes are behaviorally relevant and hampered in a model of Parkinson’s disease, we potentially provide new leads on how to develop new therapeutic strategies in the future.
Graphical summary