The effects of GPER on age-associated memory impairment induced by decreased estrogen levels

Estrogen, as a pleiotropic endocrine hormone, not only regulates the physiological functions of peripheral tissues but also exerts vital neuroregulatory effects in the central nervous system (CNS), such as the development of neurons and the formation of neural network connections, wherein rapid estrogen-mediated reactions positively stimulate spinogenesis and regulate synaptic plasticity and synaptic transmission to facilitate cognitive and memory performance. These fast non-genomic effects can be initiated by membrane-bound estrogen receptors (ERs), three best known of which are ERα, ERβ, and G protein-coupled estrogen receptor (GPER). To date, the effects of ERα and ERβ have been well studied in age-associated memory impairment, whereas there is still a lack of attention to the role of GPER in age-associated memory impairment, and there are still disputes about whether GPER indeed functions as an ER to enhance learning and memory. In this review, we provide a systematic overview of the role of GPER in age-associated memory impairment based on its expression, distribution, and signaling pathways, which might bring some inspiration for translational drugs targeting GPER for age-related diseases and update knowledge on the role of estrogen and its receptor system in the brain.