The hippocampal formation is a region of the forebrain that is important for memory and spatial navigation. On the basis of a vast amount of literature, the hippocampus is linked with long-term potentiation (LTP), the increased synaptic strength following repeated stimulation of the hippocampal neurons. LTP is considered to be the experimental demonstration of Hebb's postulate on synaptic strength and learning, and it is the dominant model of an experience-dependent modification of brain circuits. Yet, despite the importance of this phenomenon for brain physiology and behavior, little is known about how experimentally measured regional synaptic modifications alter the activity of global, widespread networks. Here, we use simultaneous fMRI, microstimulation, and electrophysiology to unveil global changes in brain activity due to local hippocampal plasticity. Our findings offer the first evidence of an LTP-induced network reorganization that includes increased interhemispheric communication and recruitment of limbic and neocortical circuits after changes in synaptic strength within the hippocampus.