Multi-electrode arrays, as efficient in vitro test-platforms to record electrical activity from excitable cells, have many advantages over conventional methods using glass microelectrodes or patch pipettes. MEAs consist of 60 to thousands electrodes that are individually and often simultaneously addressable for stimulation or recording, therefore offer excellent spatial resolution. MEAs are also particularly valuable for long-term electrophysiological studies since the planar or micronail-shaped extracellular electrodes can get close to a cell without damaging. Despite of these advantages, the use of MEAs is not yet standardized and only a few optimized protocols and applications have emerged in the field of neuroscience. This PhD project therefore aimed to develop and optimize protocols that allow us to use commercially available MEAs as well as advanced CMOS-based MEAs to study neuronal transmission and synaptic plasticity in brain tissues. In the first part of this thesis, using commercially available MEAs, we recorded synaptic transmission and plasticity simultaneously in different hippocampal subregions without cross-talk interference. We investigated early changes in synaptic function and plasticity in the CA1 and CA3 region of young APP.V717I, Tau.P301L and biAT transgenic mice as models for amyloid and/or tau-pathology in Alzheimers disease. Our findings demonstrate that long before evidence of plaque or tangle formation important subregional synaptic changes occur in the hippocampus. The MEA platform was further used to examine direct effects of human mutant tau expression on the hippocampal temporoammonic transmission in adeno-associated viral vector (AAV)-Tau.P301L injected mice. Independent recording and stimulation of the temporoammonic pathway were successfully performed. The results show that in AAV-Tau.P301L injected mice short-term plasticity in the temporoammonic pathway is significantly impaired while long-term plasticity is not affected. Finally, MEA recordings were used to characterize an Alzheimers disease animal model generated by microRNA 29a/b-1 cluster knock-out. The results of this study showed that in microRNA 29a/b-1 knock-out mice both basal and short-term synaptic transmissions are impaired while long-term potentiation is unaffected. In the second part of this thesis, we focused on developing and optimizing organotypic slice cultures integrated with complementary metal oxide semiconductor (CMOS)-based MEA surfaces to overcome limitations of acute slice applications. An automated slice tilter was developed to maintain brain slices at the interface between medium and humidified atmosphere at long-term. Slices cultured for 2 weeks showed good general viability and retained the intact hippocampal cytoarchitecture. We also found that CMOS-based high-density MEAs featuring thousands of micronail electrodes significantly enhanced initial slice adhesion therefore improved general viability compared to flat MEA surfaces. In conclusion, this work demonstrates that MEAs provide a highly stable system for the long-term monitoring of spontaneous or evoked neuronal activity in acute or organotypic brain slices and considerably improve read-out or low-throughput of conventional electrophysiological methods. In addition, the integration of organotypic brain slices with CMOS high-density MEAs is an attractive biosensor system that has the potential to address, manipulate and record electrical activity of each individual cell within a neuronal network.