<i>SELENOM</i> Knockout Induces Synaptic Deficits and Cognitive Dysfunction by Influencing Brain Glucose Metabolism

Abstract

Selenium, a trace element associated with memory impairment and glucose metabolism, mainly exerts its function through selenoproteins. <i>SELENOM</i> is a selenoprotein located in the endoplasmic reticulum (ER) lumen. Our study demonstrates for the first time that <i>SELENOM</i> knockout decreases synaptic plasticity and causes memory impairment in 10-month-old mice. In addition, <i>SELENOM</i> knockout causes hyperglycaemia and disturbs glucose metabolism, which is essential for synapse formation and transmission in the brain. Further research reveals that <i>SELENOM</i> knockout leads to inhibition of the brain insulin signaling pathway [phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR/p70 S6 kinase pathway], which may impair synaptic plasticity in mice. High-fat diet (HFD) feeding suppresses the brain insulin signaling pathway in <i>SELENOM</i> knockout mice and leads to earlier onset of cognitive impairment at 5 months of age. In general, our study demonstrates that <i>SELENOM</i> knockout induces synaptic deficits via the brain insulin signaling pathway, thus leading to cognitive dysfunction in mice. These data strongly suggest that <i>SELENOM</i> plays a vital role in brain glucose metabolism and contributes substantially to synaptic plasticity.