A fundamental question in neuroscience is how the biophysical properties of synapses shape higher network<br/>computations. The hippocampal mossy fiber synapse, formed between axons of dentate gyrus granule cells<br/>and dendrites of CA3 pyramidal neurons, is the ideal synapse to address this question. This synapse is accessible<br/>to presynaptic recording, due to its large size, allowing a rigorous investigation of the biophysical<br/>mechanisms of transmission and plasticity. Furthermore, this synapse is placed in the center of a memory<br/>circuit, and several hypotheses about its network function have been generated. However, even basic properties<br/>of this key communication element remain enigmatic. The ambitious goal of the current proposal, GIANTSYN,<br/>is to understand the hippocampal mossy fiber synapse at all levels of complexity. At the subcellular<br/>level, we want to elucidate the biophysical mechanisms of transmission and synaptic plasticity in the<br/>same depth as previously achieved at peripheral and brainstem synapses, classical synaptic models. At the<br/>network level, we want to unravel the connectivity rules and the in vivo network function of this synapse,<br/>particularly its role in learning and memory. To reach these objectives, we will combine functional and<br/>structural approaches. For the analysis of synaptic transmission and plasticity, we will combine direct preand<br/>postsynaptic patch-clamp recording and high-pressure freezing electron microscopy. For the analysis of<br/>connectivity and network function, we will use transsynaptic labeling and in vivo electrophysiology. Based<br/>on the proposed interdisciplinary research, the hippocampal mossy fiber synapse could become the first synapse<br/>in the history of neuroscience in which we reach complete insight into both synaptic biophysics and<br/>network function. In the long run, the results may open new perspectives for the diagnosis and treatment of<br/>brain diseases in which mossy fiber transmission, plasticity, or connectivity are impaired.