In Western societies, life expectancy is steadily increasing and currently around 20% of the UK’s population is over 65. Consequently, more people are suffering from age-related disorders, such as cognitive decline and neurodegeneration. It is known that the hippocampus plays a key role in learning and memory, and hippocampal damage results in cognitive deficits similar to those experienced with aging. The hippocampus is also one of the first areas of the brain to degenerate in age-related brain disorders such as Alzheimer’s disease. Thus, intense interest has focussed on the hippocampus and how its function is altered with ageing. In this respect, the cellular mechanisms underlying learning and memory and in particular hippocampal long-term potentiation (LTP) and long term depression (LTD) have been well studied.
Recent evidence indicates that reduced sensitivity to hormones are linked to age-related cognitive deficits and neurodegeneration (1). Indeed, age-related cognitive impairments in women are associated with attenuated levels of the hormone estrogen. Moreover, accumulating evidence indicates that estrogen markedly influence the processes that allow the brain to learn and remember information. Several studies indicate that estrogen also has protective actions in the brain, with reduced cell death reported in estrogen-treated neurons. However, our understanding of the cellular events underlying these age-dependent effects of estrogen are limited.
Estrogen is a steroid hormone that classically activates nuclear ERs that act as ligand-activated transcription factors. However, ERs can also initiate non-genomic responses via membrane-associated ERs. There are two well characterised ERs, ERα and ERβ which mediate most non-genomic estrogenic activity (2). However recent studies have also identified the novel orphan G-protein coupled receptor GPER1 as a target for estrogenic ligands (3) and evidence is growing that GPER1 mediates the non-genomic actions of estrogens. Recent studies have identified GPER1 expression at hippocampal synapses but our understanding of how GPER1 influences hippocampal synaptic function and how this is altered during the ageing process is limited. In this study we propose to use a combination of electrophysiology, confocal microscopy and molecular and biochemical approaches to examine in detail the impact of GPER1 activation of key cellular events underlying learning and memory, including effects on hippocampal synaptic plasticity and AMPA receptor trafficking processes, and how this is altered with age.
This study will greatly increase our knowledge of estrogen’s action in the brain and will clarify the role of GPER1 in learning and memory. This in turn may lead to development of estrogenic agents for treating age-related cognitive decline.
1. Fadel JR, Jolivalt CG, Reagan LP. (2013) Food for thought: the role of appetitive peptides in age-related cognitive decline. Ageing Res Rev. 12, 764-76.
2. McEwen B. (2002). Estrogen actions throughout the brain. Recent Prog. Horm. Res. 57, 357-84.
3. Noel SD, Keen KL, et al. (2009). Involvement of G protein-coupled receptor 30 (GPR30) in rapid action of estrogen in primate LHRH neurons. Mol. Endocrinol. 23, 349-59.