Memory consolidation in mammalian brain is accompanied by widespread reorganization of synaptic contacts and dendritic structure. Understanding of the protein-protein interactions that underlie these structural changes has been hampered by the difficulty of studying protein-protein interactions produced in vivo by signaling, learning, and other physiological responses using current methodologies. Using a novel technique that separates interacting proteins from noninteracting proteins on the basis of their protein-target affinity, we identified 16 proteins for which protein-target binding is altered in vivo by spatial learning, including stathmin, complexin I, 14-3-3, and several structural proteins including F-actin capping protein, tubulin, GFAP, and actin. Interactions between complexin and its targets (p25alpha and Drac1-like protein) and the interaction between CapZ and tubulin were calcium-dependent. The preponderance of structural proteins and proteins involved in synapse formation and reorganization of growth cones among proteins undergoing memory-specific changes in protein-protein interactions suggests that synaptic structural reorganization is a predominant feature of the consolidation phase of memory.