TARGETING NPTX1-KV7.2 AXIS MITIGATES DEFICIT OF MEMORY FORMATION VIA FACILITATING ENGRAM RECRUITMENT IN AGED MICE

Neurons with elevated intrinsic excitability are preferentially recruited into the memory engram. However, the molecular mechanisms that regulate this recruitment and a direct causal link between aging-related hyperexcitability and memory deficits remain unclear. Here, we show that neuronal pentraxin 1 (NPTX1), the biomarker for neurodegeneration, functions as a key molecular brake that restrains hyperexcitability in the dentate gyrus (DG) neurons. NPTX1 knockdown in young mice increases intrinsic excitability, enhances excitatory synaptic transmission, and enlarges mushroom spine heads, ultimately impairing the recruitment of c-Fos⁺ engram and the formation of contextual fear memory. In 24-month aged mice, a downregulation of Nptx1 and a corresponding increase in DG neuronal excitability were observed, which together contribute to the deficits in engram recruitment and memory performance. Overexpression of NPTX1 in aged DG rescues these deficits by normalizing neuronal excitability. Pharmacological activation of Kv7.2, an interaction partner of NPTX1, achieved comparable rescue effects. Our study establishes NPTX1 as a critical regulator of engram cell eligibility and highlights the NPTX1-Kv7.2 axis as a promising therapeutic target for aging-related memory impairment.