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Cellular determinants of neuronal plasticity on the level of single synapses in vivo

Final Report Summary - INVIVOSYNAPSE (Cellular determinants of neuronal plasticity on the level of single synapses in vivo)

This project was focused on the improvement of our in vivo understanding synaptic functions in brain neurons in health and disease. Since cellular studies are not feasible in humans, we relied in most of our experiments on mouse models. A major effort was dedicated to constantly improving our methods in order to overcome current technical limitations. The major technical advances in this project include the development of a new method of ‘deep’ two-photon calcium imaging of neuronal networks. With this method we were for the first time able to analyze entire cortical regions, such as the auditory or the visual cortex, from the top down to deepest layer 6 with single cell and single action potential resolution. The results obtained with this method include the generation of the most complete functional map of a cortical column at single-neuron resolution in vivo. Another technical development was the improvement of single synapse imaging in vivo. By developing approaches of two-photon spine imaging in vivo, involving both chemical and genetically-encoded calcium indicators, we provided detailed characterizations of single synapses of layer 2/3, layer 4 and layer 5 cortical neurons. Furthermore, a new developed method of optical fiber photometry was the basis of a study in which we discovered a visual cue-dependent brain circuit for place memory and navigation. On the level of larger scale cortical circuits, a major effort was devoted to a better understanding of the cellular mechanisms underlying brain-wide slow oscillations. Such slow oscillations occur during sleep and play a crucial role for the consolidation of recent memories. We demonstrated that in Alzheimer’s disease, slow oscillations are massively impaired. This impairment can directly affect the learning ability of the patients. Our results revealed the synaptic mechanism causing the breakdown of slow oscillations and demonstrated that they consist of a pathological reduction in synaptic inhibition. We could demonstrate that pharmacological treatments that strengthen synaptic inhibition can rescue both the impaired sleep oscillations and the learning deficits. In an additional study, we obtained a cellular explanation for the failure of immunotherapy in most human studies. These results suggested new experimental strategies for the development of more effective treatments of Alzheimer’s disease. Indeed, we provide experimental evidence that, for example, the pharmacological manipulation of the β-secretase BACE, a key enzyme involved in the generation in toxic brain compound Aβ, can be a promising therapeutical strategy in Alzheimer’s disease.