Micro-COPS developed multiple complex new approaches to study MG and neuron biology - e.g. (i) an electrophysiological secretion assay based on light-mediated calcium uncaging and cell capacitance measurements, (ii) a cell lineage tracing assay to assess the origin and fate of MG cells and the effect of neuronal activity, (iii) novel microscopic and imaging methods to study MG biology, (iv) a theoretical framework that links the function of synapses between nerve cells to the number of transmitter receptors, or (v) a novel method to visualize optogenetically stimulated synapses in the EM, which allows to compare the ultrastructure of potentiated synapses to their neighbours on the same dendrite or axon. Further, Micro-COPS generated multiple new genetically modified mouse lines that (i) allow to follow gene expression and transcriptional control in MG, (ii) modulate levels of intracellular second messengers, or (iii) allow to optogenetically induce changes of the intracellular second messenger cAMP in MG. Micro-COPS identified a novel, activity-dependent, neuromodulatory feedback process, where MG sense neuronal activity via neuronal transmitters and in turn suppress neuronal activity. This mechanism protects the brain from excessive activation, may play a major role in maintaining physiological sleep behaviour, and may regulate neuronal responses to sensory inputs. Indeed, this process plays a key role in maintaining neuronal activity-induced changes in blood flow. Micro-COPS also identified a novel MG population in a brain region called the striatum, which controls movements and behaviour in response to the release of the neurotransmitter dopamine. This MG subpopulation expresses the dopamine D1 receptor and plays a critical role in dopamine-induced neuronal function and dopamine-dependent behaviours, such as addiction. Furthermore, Micro-COPS discovered that MG release the messenger TNFα and thereby regulate the function and plasticity of synapses between nerve cells. This process involves massive changes in the modification of cellular proteins via phosphorylation and plays a key role in the control of sleep. In addition, we developed a mouse model that expresses Gq-DREADD under the control of an inducible MG-specific promoter. This model allows to selectively activate MG without affecting other brain cell types. Using these mice, Micro-COPS discovered that specific activation of MG profoundly affects the synapses between nerve cells, specifically their stability, and thereby controls learning and memory. Finally, we found that MG Gq activation protects mice against stroke-related tissue damage and improves behavioural recovery. This finding has major relevance for our understanding of stroke-related brain damage and potential new therapeutic approaches.
