Gene expression in adult neuronal circuits is dynamically modulated in response to synaptic activity. Persistent changes in synaptic strength, as seen during high-frequency stimulation (HFS)-induced long-term potentiation (LTP), require new gene expression. While modulation of many individual genes has been shown, an understanding of LTP as a complex dynamical response requires elucidation of the global gene expression signature and its impact on biologically meaningful gene sets. In this study, we demonstrate that LTP induction in the dentate gyrus of awake freely moving rats was associated with changes in the expression of genes linked to signal transduction, protein trafficking, cell structure and motility, and other processes consistent with the induction of mechanisms of synaptic reorganization and growth. Interestingly, the most significantly over-represented gene sets were related to immunity and defense, including T-cell-mediated immunity and major histocompatibility complex (MHC) class I-mediated immunity. Real-time PCR confirmed the upregulation of a panel of immune-linked genes including the rt1-a/ce family, and the MHC class II members cd74, rt1-Ba and rt1-Da. These genes were N-methyl-d-aspartate receptor-independent and not induced following HFS-LTP induction in anesthetized rats, indicating a gene response specific to behaving rats. Our data support recent assumptions that immunity-associated processes are functionally linked to adaptive neuronal responses in the brain, although the differential expression of immunity-linked genes could also be related to the HFS per se.