Hippocampal Dipeptidyl Peptidase 9 Bidirectionally Regulates Memory Via Synaptic Plasticity

It has been reported that peripherally expressed subtypes of the dipeptidyl peptidase (DPP) family, such as DPP4, modulate memory. However, interestingly whether DPP9 which one of the central nervous systems (CNS) enriched isoforms, regulates memory has not been elucidated yet. Here, we report that DPP9, which is found almost exclusively in neurons, is highly expressed and has high enzyme activity in many brain regions, especially in the hippocampus. Hippocampal DPP9 expression increases after fear memory formation. Fear memory was weakened by DPP9 knockdown and enhanced by DPP9 protein overexpression in the hippocampus. According to subsequent hippocampal proteomics, multiple pathways were enriched by DPP9 expression changes, including the peptidase pathway, which can be bidirectionally regulated by DPP9, and pathways involved in the regulation of synaptic plasticity. DPP9 interacts with its enzymatic substrate neuropeptide Y (NPY) in neurons directly. Hippocampal long-term potentiation (LTP), a form of synaptic plasticity, further confirmed the key role of DPP9 in decreasing LTP through DPP9 knockdown and enhancing LTP through its overexpression. Moreover, inhibiting DPP9 enzyme activity impairs both plasticity and memory. Besides, Affinity purification mass spectrometry (AP-MS) revealed that DPP9-interacting proteins are involved in the functions of dendritic spines and axons. By combining AP-MS and proteomics, DPP9 was shown to play a role in regulating actin functions. Taken together, our findings reveal that DPP9 affects the CNS not only through enzymatic activity but also through protein‒protein interactions. This study provides new insights into the molecular mechanisms of memory and DPP family functions. ### Competing Interest Statement The authors have declared no competing interest.