Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Dipeptidyl peptidase (DPP) family members, like DPP4, are linked to memory deficits.
• DPP9 is prevalent in the brain, but its role in memory regulation is unknown.

Purpose of the Study:

• To investigate the function of DPP9 in memory processes.
• To uncover the molecular mechanisms underlying DPP9's effects on memory.

Main Methods:

• Immunofluorescence to map DPP9 distribution in mouse brains.
• Adeno-associated virus (AAV) vectors for DPP9 knockdown and overexpression models.
• Behavioral tests, electrophysiology, proteomics, and affinity purification mass spectrometry (AP-MS) to assess memory and molecular interactions.

Main Results:

• DPP9 is primarily in neurons, with high expression and activity in the hippocampus, increasing after fear memory formation.
• Hippocampal DPP9 knockdown impaired memory, while overexpression enhanced it.
• DPP9 directly interacts with neuropeptide Y (NPY) and regulates long-term potentiation (LTP) and actin dynamics, affecting dendritic spines and axons.

Conclusions:

• DPP9 influences central nervous system (CNS) functions via enzymatic activity and protein interactions.
• This study offers novel insights into memory mechanisms and the broader functions of the DPP family.