Peripheral Substance P Induces Deficits in Hippocampal Synaptic Plasticity and Memory

Substance P (SP) is a neuropeptide that functions in both the central and peripheral nervous systems. Although SP-containing neurons convey nociceptive information to the spinal cord and regulate inflammatory responses in peripheral tissues, the impact of a peripheral increase in SP on hippocampal functions, such as spatial learning and memory, remains unclear. In this study, we found that male mice subcutaneously injected with SP for 14 days exhibited significant deficits in hippocampus-dependent memory, as assessed by the object place recognition and novel object recognition tests. In addition, long-term potentiation (LTP) at the hippocampal CA3–CA1 synapse was reduced in SP-treated mice. Transcriptomic analyses identified 77 differentially expressed genes (DEGs), and enrichment analysis highlighted pathways related to synaptic transmission, learning, and memory. These results suggest a novel skin–brain neuropeptide signaling axis. Targeting peripheral SP or its receptor may provide a therapeutic avenue for cognitive dysfunction associated with peripheral inflammation.