Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice

As estrogen levels decline with aging and menopause, the protective influence of mERα/Cav1 may diminish, unmasking the oAβ-induced suppression of GIRK channel activity and exacerbating disease progression in females. While amyloid β plaques (Aβ) are notable hallmarks of Alzheimer's Disease (AD), cognitive impairment in the early stages of the disease tracks more closely with the level of soluble Aβ oligomers (oAβ) in the brain. oAβ promotes cognitive deficits by disrupting the balance of excitatory and inhibitory influences on neurons in brain regions important for learning and memory such as the hippocampus, but the underlying molecular targets of oAβ and its pathogenic mechanisms are not fully understood. We recently demonstrated that oAβ weakens the activity of a prominent inhibitory influence on neuronal excitability (the GIRK channel) in the hippocampus of male but not female mice. This sexually dimorphic effect of oAβ was interesting and unexpected given that women are twice as likely to develop AD than men, and because disease progression is more aggressive in women. In this study, we investigated the mechanisms underlying the resilience of GIRK channels in female hippocampal neurons to oAβ. We found that resilience is conferred by estrogen and one of its receptors. When the influence of this receptor is diminished using pharmacological or genetic interventions, oAβ weakens GIRK channel activity in female and male neurons to a similar degree, and via the same mechanism. We speculate that with the onset of menopause, the protective influence of estrogen on GIRK channel activity in the hippocampus begins to wane. This, combined with other female-specific effects of oAβ on neuronal activity, contributes to the increased incidence and severity of AD in females.