Alzheimer’s disease is characterized by two hallmarks, extracellular Ab-deposition and intracellular aggregation of hyperphosphorylated tau. Furthermore, synapse and neuron loss correlates well with cognitive decline. Sterile inflammation carried out by microglia that are part of the innate immune system in the brain, are in the focus of current research. We try to understand how these components contribute to learning and memory deficits under AD-like conditions. On the one hand, we investigate the hypothesis that an imbalance of excitation and inhibition related to synapse and neuron dysfunction contributes to neuronal network disturbance. In this direction we investigate how structural and functional deficits of GABAergic neurons in the hippocampus contribute to learning and memory deficits. On the other hand, we investigate how microglia contribute to synaptic and neuronal deficits. Especially, we are interested in the interaction of microglia with individual synapses and neurons and how that impacts on the integrity neuronal network connectivity. To address these questions we use state of the art in vivo imaging techniques and combine them with electrophysiological, histological and biochemical techniques in transgenic mice. Moreover, we use optogenetics and chemogenetics to specifically activate or inactivated neuronal subsets.