Title: Synaptic signatures of hippocampal memory engrams

Abstract:
Enhanced synaptic wiring onto sparsely distributed memory engram cells is crucial for
contextual memory storage and recall, with negative valence memories being more salient. This learning dependent augmentation of connectivity is shaped by alterations in synapse physiology, morphometry and molecular composition. While recent work has identified structural trajectories, the protein landscape of hippocampus CA1 engram cell synapses remains largely unknown. Using a combination of spatiotemporally controlled synapse labelling, sorting and sensitive mass spectrometry, we mapped the proteome of CA1 engram cell synapses receiving CA3 input 72 h after either neutral context exploration or aversive contextual fear conditioning. Our data identify experience-dependent protein expression profiles linked to enhanced engram connectivity. Notably, aversive learning is characterised by dominant postsynaptic signatures, while neutral context skews towards the presynapse. Finally, we demonstrate that protein expression and localisation patterns may relate to whether the presynaptic partner of an engram cell is also an engram cell or not. Together, our data provide a comprehensive molecular correlate of hippocampal engram cell synapses encoding experience-dependent contextual memory.