The results from the present investigation highlight key molecular and cellular alterations in the hippocampus of animals exposed to periodontitis and CMS, including upregulation of the pro‐inflammatory TLR‐4 signaling pathway, reduced microglial density coupled with the induction of an activated phenotype, downregulation of the BDNF signaling pathway, and decreased levels of the synaptic plasticity‐associated protein synaptophysin (see graphical abstract). This evidence concerns the gene SYP and periodontitis.