LAUSR

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques and cognitive decline, the latter of which is thought to be driven by soluble oligomeric amyloid-β (oAβ). The dysregulation of G protein–gated inwardly rectifying K+ (GIRK; also known as Kir3) channels has been implicated in rodent models of AD. Here, seeking mechanistic insights, we uncovered a sex-dependent facet of GIRK-dependent signaling in AD-related amyloid pathophysiology. Synthetic oAβ1–42 suppressed GIRK-dependent signaling in hippocampal neurons from male mice, but not from female mice. This effect required cellular prion protein, the receptor mGluR5, and production of arachidonic acid by the phospholipase PLA2. Although oAβ suppressed GIRK channel activity only in male hippocampal neurons, intrahippocampal infusion of oAβ or genetic suppression of GIRK channel activity in hippocampal pyramidal neurons impaired performance on a memory test in both male and female mice. Moreover, genetic enhancement of GIRK channel activity in hippocampal pyramidal neurons blocked oAβ-induced cognitive impairment in both male and female mice. In APP/PS1 AD model mice, GIRK-dependent signaling was diminished in hippocampal CA1 pyramidal neurons from only male mice before cognitive deficit was detected. However, enhancing GIRK channel activity rescued cognitive deficits in older APP/PS1 mice of both sexes. Thus, whereas diminished GIRK channel activity contributes to cognitive deficits in male mice with increased oAβ burden, enhancing its activity may have therapeutic potential for both sexes. Male mice show amyloid-β–induced GIRK channel dysregulation in early stages of Alzheimer’s disease. Editor’s summary Early stages of Alzheimer’s disease (AD) are associated with amyloid-β (Aβ) deposition and enhanced neuronal excitability, and loss of inhibitory G protein–gated K+ (GIRK) channel activity has been implicated in rodent AD models. Luo et al. identified a sex-dependent mechanism by which Aβ oligomers suppressed GIRK channel activity in hippocampal neurons. Whereas this mechanism was evident before onset of cognitive deficits only in male AD model mice, genetic enhancement of GIRK channel activity improved cognitive performance in older male and female mice. Thus, GIRK channels may be a sex-dependent driver of early AD pathology but a potential sex-independent target for therapy in later-stage patients. —Leslie K. Ferrarelli