Progressive reduction of nuclear receptor Nr4a1 mediates age‐dependent cognitive decline

Abstract INTRODUCTION Cognitive decline progresses with age, and Nr4a1 has been shown to participate in memory functions. However, the relationship between age‐related Nr4a1 reduction and cognitive decline is undefined. METHODS Nr4a1 expressions were evaluated by quantitative PCR and immunochemical approaches. The cognition of mice was examined by multiple behavioral tests. Patch‐clamp experiments were conducted to investigate the synaptic function. RESULTS NR4A1 in peripheral blood mononuclear cells decreased with age in humans. In the mouse brain, age‐dependent Nr4a1 reduction occurred in the hippocampal CA1. Deleting Nr4a1 in CA1 pyramidal neurons (PyrNs) led to the impairment of cognition and excitatory synaptic function. Mechanistically, Nr4a1 enhanced TrkB expression via binding to its promoter. Blocking TrkB compromised the cognitive amelioration with Nr4a1‐overexpression in CA1 PyrNs. DISCUSSION Our results elucidate the mechanism of Nr4a1‐dependent TrkB regulation in cognition and synaptic function, indicating that Nr4a1 is a target for the treatment of cognitive decline. Highlights Nr4a1 is reduced in PBMCs and CA1 PyrNs with aging. Nr4a1 ablation in CA1 PyrNs impaired cognition and excitatory synaptic function. Nr4a1 overexpression in CA1 PyrNs ameliorated cognitive impairment of aged mice. Nr4a1 bound to TrkB promoter to enhance transcription. Blocking TrkB function compromised Nr4a1‐induced cognitive improvement.