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 substance P-containing neurons convey nociceptive information to the spinal cord and regulate inflammatory responses in peripheral tissues, the impact of a peripheral rise in substance P on hippocampal functions such as spatial learning and memory remains unclear. Here, we show that chronic peripheral substance P significantly impaired performance in both the object place recognition (OPR) and novel object recognition (NOR) tests compared to saline controls. Electrophysiology revealed a marked reduction in CA3‑CA1 LTP without changes in basal synaptic transmission. RNA‑Seq identified 77 differentially expressed genes (DEGs), and enrichment analysis highlighted pathways related to synaptic transmission and learning/memory. Male C57BL/6N mice were subcutaneously injected with substance P (10 µM, 100 µL) for 14 days. Hippocampus‑dependent behaviours (OPR, NOR) and CA3‑CA1 long-term potentiation (LTP) were assessed. RNA‑Seq was performed on hippocampal tissue, and DEGs were analysed.