Intracellular accumulation of neurofibrillary tangles and senile plaques formed by the extracellular deposit of cerebral amyloid-ß (Aß) peptide oligomers are the classical pathological hallmarks of Alzheimer's disease (AD) and lead ultimately to neuronal cell death. However, it has become clear more recently that soluble Aß disrupt glutamatergic synaptic function, which in turn leads to the characteristic cognitive deficits already present at early stages of AD. In addition, soluble Aß is a potent activator of microglia and astrocytes leading to the production and the release of a whole array of inflammatory molecules which in turn affect synaptic transmission and plasticity. There are two main inter-connected objectives to the projectwith the final aim to provide a rationale for the test and discovery of new therapeutic strategies to alleviate cognitive deficits that precede neurodegeneration in AD. First we will provide a comprensive view of the structural and functional changes that occur at a central glutamatergic synapse during aging in two mouse models of AD. We will focus on synaptic transmission in pyramidal cells in the hippocampal CA3 area, a brain region critically involved in the encoding of novel information. Within this frame we shall ask the following fundamental questions : does chronic accumulation of Aß-peptides over the progressive development of the disease impair synaptic structure, function and plasticity in the CA3 region of the hippocampus, a region critically involved in the encoding of novel information? Second, we will study how neuroinflammatory processes participate in the progressive synaptic failure linking to cognitive deficits. Although it is well established that the neuroinflammation process participates both to the onset and the chronicity of AD, precise mechanisms linking neuroinflammation with glutamatergic synaptic disruption have not yet been explored. Is there a link between neuroinflammatory processes and synaptic dysfunction? This project is a basic research project that will shed light on the pathological aging process in a brain region implicated in the encoding of novel information. However, we also plan to set the experimental conditions for examining how currently used therapeutic approaches (such as anti-inflammatory drugs or memantine) prevent all or part of the synaptic symptomatology found in AD transgenic mice. We will test if it possible to restore normal synaptic structure and function by chronic treatments with currently used therapeutic approaches (such as memantine), or new antiinflammatory molecules? The "synaptic failure" hypothesis of AD has received much less attention in France than in countries like UK or the United States. This is likely changing now given the high potential of drugs which could alleviate synaptic deficits in the early phase of the cognitive decline in AD. Our group has no previous participation in the field of AD, but it endeavours to durably make the field benefit from our strong expertise in synaptic electrophysiology and cell biology.