| First Author | Luo H | Year | 2024 |
| Journal | Sci Signal | Volume | 17 |
| Issue | 856 | Pages | eado4132 |
| PubMed ID | 39353038 | Mgi Jnum | J:360165 |
| Mgi Id | MGI:7787209 | Doi | 10.1126/scisignal.ado4132 |
| Citation | Luo H, et al. (2024) Amyloid-beta oligomers trigger sex-dependent inhibition of GIRK channel activity in hippocampal neurons in mice. Sci Signal 17(856):eado4132 |
| abstractText | 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-beta (oAbeta). 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 oAbeta(1-42) 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 PLA(2). Although oAbeta suppressed GIRK channel activity only in male hippocampal neurons, intrahippocampal infusion of oAbeta 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 oAbeta-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 oAbeta burden, enhancing its activity may have therapeutic potential for both sexes. |
