Synaptic signaling networks encode experience by assuming stimulus-specific and brain-region-specific states

A core network of ubiquitously expressed glutamate-synapse-associated proteins mediates activity-dependent synaptic plasticity throughout the brain, but the specific proteomic composition of synapses differs between brain regions. Here, we sought to classify the diversity of activity-dependent remodeling across brain regions using quantitative protein interaction network (PIN) analysis. We first compared the response of cultured neurons to distinct stimuli, and defined PIN parameters that differentiate input types. We next compared the response of three different brain regions maintained alive in vitro to an identical stimulus, and identified three qualitatively different PIN responses. Finally, we measured the PIN response following associative learning tasks, delay and trace eyeblink conditioning, in three brain regions, and found that the two forms of associative learning are distinguished from each other using brain-region-specific network mechanisms. We conclude that although the PIN of the glutamatergic post-synapse is expressed ubiquitously, its activity-dependent dynamics show remarkable stimulus-specific and brain-region-specific diversity. ### Competing Interest Statement The authors have declared no competing interest.