Age-dependent increases in dorsal hippocampal postsynaptic α5GABA-a receptors may be lost in a rat model of Alzheimer's disease.

Targeting amyloid for inhibition of neurodegeneration and cognitive decline in Alzheimer’s Disease (AD) using selective therapeutics has been mildly successful, but an improved understanding of memory dysfunction on a neural circuitry level may be needed for development of acute nootropics for ongoing memory dysfunction. Here, we focus on the hypothesis that if early onset memory decline can be traced to the hippocampal trisynaptic circuit, then it could serve as a target for therapeutic modulation. Inhibitory GABAergic neurons participate in sharp wave ripple (SPW-R) oscillations in the hippocampal trisynaptic circuit as detected in CA1 during sleep and awake inactivity and are believed to function in memory replay and consolidation. Using the transgenic beta amyloid expressing TgF344-AD rat, which develops frank neurodegeneration and memory impairment with age, we previously discovered that ripple amplitude in 9mo and older TgF344-AD rats are insensitive to the nootropic drug α5IA, a negative allosteric modulator of α5-subunit containing γ-aminobutyric acid type A receptors (α5GABA(A)Rs). Here, we ask whether the loss of α5IA potentiation of ripple amplitude might reflect AD-specific downregulation of the predominant extrasynaptic α5GABA(A)R isoform. To our surprise, however, postsynaptic α5GABA(A)R levels decrease with aging in the dorsal dentate gyrus (DG) of TgF344-AD while increasing in wt littermates. The results support a model wherein age-associated beta-amyloid inhibits α5GABA(A)R trafficking. We posit that reducing α5GABA(A)R trafficking in excitatory specifically to the postsynaptic compartment in dorsal DG, and likely in CA1 neurons, may reduce their ability to shape local field potentials, including ripples, and blunt the pharmacological action of α5IA on ripple amplitude. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-025-28973-9.