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Project Summary

Activation of microglia in primary lesion sites has been reported in many brain diseases. Less understood remains the relevance of microglia in denervated brain regions, which loose part of their input without being directly affected by the disease. It is clear, however, that the structural and functional reorganisation of denervated networks contributes to the clinical symptoms of brain diseases. In work leading to this proposal, we were able to demonstrate that microglia are activated in denervated (but otherwise healthy) brain regions and that denervated neurons respond to the loss of input with a compensatory increase in excitatory synaptic strength. This homeostatic property of neurons is fundamental for the functioning of neuronal networks and has been suggested as a target for therapeutic intervention. We here propose to study the role of microglia in mediating homeostatic synaptic plasticity. To address this question, we will exploit the well-described connectivity and laminated cytoarchitecture of the hippocampus, which allows for the input-/lamina-specific denervation of CA1 pyramidal neurons in entorhinal-hippocampal tissue cultures. This way, we will (i) investigate input-/lamina-specific responses and the dynamics of microglia-neuron interactions under control conditions and following denervation, (ii) study the role of microglial regulatory signals that mediate local homeostatic synaptic responses (i.e.,IL-1, TNFα, IL-6), and (iii) we will test whether non-invasive modulation of neuronal  activity (under control conditions and after the partial loss of input), in turn, influences microglia activity and function. In collaboration with our NeuroMac partners our experiments will provide new important information on the role of microglia in mediating synaptic homeostasis, which is of considerable relevance in the context of brain diseases associated with neuronal cell death and subsequent disconnection.