Storage and recall of information depend on multiple forms of activity-dependent synaptic and intrinsic plasticity processes with distinct temporal dynamics. Within the hippocampus, a myriad of studies have focused on long-term changes in synaptic efficacy occurring on the postsynaptic side. In contrast, the cell-biological mechanisms and the functional consequences of presynaptic plasticity have been much less explored than postsynaptic forms of plasticity, in particular in relation to memory. We hypothesize that structural and functional plasticity on the presynaptic side, acting in a concerted fashion, shape the dynamics of neural processing in hippocampal circuits, which ultimately underlies mechanisms of memory encoding and recall. This line of thinking fills an important but largely unexplored research area, as previous studies considered either structural or functional plasticity in isolation but not both together, and have mostly focused on long-term postsynaptic forms of plasticity. Presynaptic forms of plasticity provide a highly dynamic mechanism to act on information transfer and circuit function, at different times scales ranging from hundreds of milliseconds to days. In addition, the morphology and stability of excitatory and inhibitory synapses (including presynaptic terminals) is highly variable over time, in particular in relation to learning. Here we will examine the mechanisms by which two essential presynaptic molecular components, Syt7 and GluK2, contribute to presynaptic plasticity at identified synapses in the hippocampus. In addition, we will investigate how the close interplay between presynaptic functional and structural plasticity determines the dynamics of information processing, encoding and retrieval in a memory-related brain region. We choose to focus on the CA3 region of the hippocampus, a key region for the early stages of memory acquisition, and in particular on DG-CA3 connections which constitute a major entry point from the cortex to the hippocampus. The following questions will be addressed: Aim 1. What are the subcellular mechanisms of short-term facilitation at DG-CA3 connections? Mf–CA3 PC synapses display a wide spectrum of functional plasticity and these connections serve as an excellent model for structure-function analyses of presynaptic plasticity. Aim 2. What are the dynamic features and mechanisms of structural plasticity at Mf-CA3 synapses? We want to clarify the activity-dependence of presynaptic structural plasticity, and understand the potential impact of memory encoding and processing on the morphology of Mf terminals. Aim 3. How do the two modalities of presynaptic plasticity combine to determine information processing and memory function in CA3? How does presynaptic plasticity impact information transfer and local CA3 circuit function (including excitation/inhibition balance) in vivo? What consequences on brain oscillations and brain state at a single cell and neural ensemble level? Is presynaptic plasticity involved in memory encoding and retrieval? The PREPLASH project is a basic science project aiming at understanding the mechanisms and functional consequences of presynaptic plasticity in a hippocampal circuit within the frame of memory. It is closely related to the themes of CES 16. Understanding the cellular and molecular mechanisms of neural plasticity remains one of the most important challenges for neuroscience research. Through the combined application of innovative experimental and analytical approaches, the project is likely to reveal new plasticity mechanisms, thereby fostering new insights into basic brain mechanisms. We are confident that the results obtained will be of high interest in the field of neuroscience, and will further fuel theories on brain mechanisms of information storage and recall