Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer’s molecular signatures

Significance The excitatory amino acid transporter 2 (EAAT2) is the predominant glutamate transporter in the mammalian brain, and its expression is reduced in aging and sporadic Alzheimer’s disease (AD) brains. The mechanisms through which reduced EAAT2 expression contributes to cognitive decline and AD-related neurodegeneration and the differential functional roles of its astrocytic and neuronal components remain largely unknown. This study uses behavioral analysis to show that astrocytic and neuronal EAAT2 deficiency in mice causes age-dependent cognitive dysfunction. Furthermore, we show that gene expression from human AD and aging datasets have a robust overlap with astrocytic EAAT2 deficiency. This study highlights the distinct signaling mechanisms mediated by neuronal and astrocytic EAAT2 and EAAT2 as a potential therapeutic target in aging and AD.