Hippocampal Dipeptidyl Peptidase 9 Bidirectionally Regulates Memory Via Synaptic Plasticity

Abstract

Dipeptidyl Peptidase family members are known to modulate memory through peripheral substrates. However, the direct impact of this family on the central nervous system (CNS) remains underexplored. Dipeptidyl peptidase 9 (DPP9) has been extensively studied for its role in inflammation and cancer. Here, we found that DPP9 is relevant highly expressed in hippocampal neurons. Electrophysiological and behavioral experiments have shown that it plays a pivotal role in long-term potentiation and memory. Proteomics analysis identified differentially expressed proteins associated with memory retrieval regulated by DPP9. Further investigation revealed that DPP9 enzymatic activity is essential for memory retrieval. DPP9-interacting proteins are involved in the function of the dendritic spine and axon, and two memory- and axon-related genes, Tmp3 and Baiap2, were identified as potential targets for DPP9. Our findings suggest that DPP9 is a novel memory regulatory protein and provide new insights into memory molecular mechanisms.