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

SUMMARY

A core network of widely expressed proteins within the glutamatergic post-synapse mediates activity-dependent synaptic plasticity throughout the brain, but the specific proteomic composition of synapses differs between brain regions. Here, we address the question, how does proteomic composition affect activity-dependent protein-protein interaction networks (PINs) downstream of synaptic activity? Using quantitative multiplex co-immunoprecipitation, we compare the PIN response of in vivo or ex vivo neurons derived from different brain regions to activation by different agonists or different forms of eyeblink conditioning. We report that PINs discriminate between incoming stimuli using differential kinetics of overlapping and non-overlapping PIN parameters. Further, these “molecular logic rules” differ by brain region. We conclude that although the PIN of the glutamatergic post-synapse is expressed widely throughout the brain, its activity-dependent dynamics show remarkable stimulus-specific and brain-region-specific diversity. This diversity may help explain the challenges in developing molecule-specific drug therapies for neurological disorders.

Graphical Abstract

In brief

Molecular encoding of sensory stimuli occurs through modification of synaptic protein networks, but the underlying rules are poorly defined. Lautz et al. demonstrate that four brain regions respond to eyeblink conditioning by modifying excitatory synapse protein interaction networks using different encoding strategies, despite employing a similar set of proteins.