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The present project explores a novel approach and research focus at different levels, using innovative and clinically valid tests of murine cognition, neuronal plasticity measures, brain lesion methods, neurocognitive test batteries and in vivo neuroimaging. Since human neuropsychology is very different from animal testing, the primary goal of this dissertation is to increase the fundamental knowledge about early deficits in prefrontal cortex (PFC) and hippocampus (HC) functioning in mouse models of AD, since these two brain regions are known to be the first most affected in the neuropathology of AD. Consequently, the PFC/HC pathway might be considered as a valuable target for therapeutic intervention in further animal research. Although quite elaborate from a technical point of view, we have implemented these different methodologies because we wanted to investigate as detailed as possible the involvement of the PFC and HC in a central and clinically relevant aspect of cognitive functioning during early stages of Alzheimer’s disease. This work includes several innovative aspects that have not been extensively investigated before. First, our focus on cognitive flexibility, which is an aspect of executive functioning. For example, we used not only the well-established reversal learning protocol in the MWM but also a relatively new protocol to examine executive functioning in AD models. Second, most research on cognitive functioning in mouse models of AD has used transgenic mice at ages when the typical neuropathological changes are fully established. This study, however, focuses on cognitive changes in an earlier stage when NFT’s and Aβ have not yet fully formed. Moreover, these transgenic mice contain intrinsic problems that may induce artificial phenotypes, leading to misconceptions about AD pathology. To circumvent these problems we have used novel mouse models that overproduce Aβ42 without overexpressing APP in order to identify discrete factors involved in AD pathology.Third, PFC/HC connectivity is of considerable current interest and subject of much research in human neuroimaging and rodent electrophysiology, but the detailed BOLD functional connectivity signature of these anatomical structures had not been elucidated so far in the PFC lesion and AD mouse models. We hypothesized that PFC and HC neural network controls cognitive flexibility and that this network is often affected in early stages of neurodegenerative pathologies altering in turn synaptic functioning. The aims of this PhD thesis are (1) to characterize the role of PFC and HC circuitry in the early stages of neurodegeneration in chemical and genetic mouse models; (2) to examine whether changes in learning-related synaptic plasticity and in vivo functional connectivity correlate with particular aspects of AD neuropathology; and (3) to test the validity of novel electrophysiology tools to investigate synaptopathies as well as study the effect of mGluRs and GSK3β inhibitors, which can be used in preclinical and translational research using AD models.