Plasticity of glutamatergic synapses is considered to be a pivotal mechanism underlying the ability of the CNS to re-configure its neural circuits. A large number of studies have focused on investigating how individual proteins, biochemical pathways and structural processes alter both the induction and maintenance of synaptic plasticity. However, it is likely that synaptic plasticity involves temporally and spatially coordinated regulation of multiple protein complexes within the activated neural circuit. By using a global proteomics-based approach we have now been able to reveal that highly diverse protein classes exhibit altered expression in response to both the activation of glutamate receptors and the induction of long-term potentiation (LTP) of glutamatergic synaptic strength in the hippocampus; a brain area where plastic synaptic modification is believed to be key to cognitive processes, such as spatial learning. Of the 2946 resolvable protein spots detected in this study, 79 (2.7%) were significantly altered in abundance in response to 100 microM glutamate application (all P < 0.05). The majority (56 out of 79) of these changes were due to the activation of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptor. Likewise, the induction of LTP was associated with an altered abundance of 2.4% of the detectable proteome during the early (10 min) phase and 1.7% during the late (4 h) phase of its development. Observed changes in temporal and protein class-specific patterns of expression depict a widespread shift from metabolic to structural protein alteration as the plasticity process matures.