The full-length amyloid precursor protein (APP), a key player in Alzheimer’s disease (AD), is ubiquitously expressed throughout the brain. It is known to be abundantly expressed in presynaptic compartments where it interacts with proteins of the presynaptic release machinery. However, the physiological functions of APP in the CNS still remain to be investigated. Here we study the physiological role of APP in presynaptic plasticity and information transfer within the hippocampus. We deleted APP and the related protein APLP2 in dentate gyrus granular cells (GCs) using a viral gene transfer strategy in APP/APLP2 double floxed mice. By combining optogenetics and ex vivo electrophysiology, we found that the selective deletion of APP in GCs impairs presynaptic short‑term plasticity at mossy-fiber (MF) to CA3 pyramidal cells synapses, without altering the intrinsic spiking properties of GCs. Additionally, the sustainability of post-tetanic potentiation seems to be hindered by the lack of APP. We are currently addressing the molecular mechanisms by which APP controls presynaptic short-term plasticity. To do so, we purified GFP-labelled MF‑CA3 synaptosomes using Fluorescence Activated Synaptosome Sorting, in order to perform a comparative proteomic screening to identify presynaptic proteins dysregulated in the absence of APP. Altogether, our data supports a role of presynaptic APP in synaptic transmission and plasticity mechanisms at the MF-CA3 synapse. We propose that shedding light on the physiological contribution of full-length APP to hippocampal circuit activity will help understanding how disruption of APP functions contributes to the pathophysiology of AD.