Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples in Alzheimer’s disease

Decades of research attempting to slow the onset of Alzheimers disease (AD) indicates that a better understanding of memory will be key to the discovery of effective therapeutic approaches. Here, we ask whether prodromal neural network dysfunction might occur in the hippocampal trisynaptic circuit by using 5IA as a selective negative modulator of extrasynaptic 5GABA-A receptors in TgF344-AD transgenic rats, a model for early onset AD. The results demonstrate that orally bioavailable 5IA, an established memory enhancer, increases CA1 pyramidal cell mean firing rates and peak CA1 ripple amplitude during wakeful immobility in wild type F344 rats resting in a familiar environment. We show that TgF344-AD rats, which express human amyloid-beta precursor protein (with the Swedish mutation) and human presenilin-1 (with a {Delta} exon 9 mutation), exhibit high serum A{beta}42 and A{beta}40 levels by 3 months of age. By 9 months of age, CA1 ripples in young adult TgF344-AD rats are nonresponsive to 5IA indicating network dysfunction prior to the onset of AD pathology and memory dysfunction. These results demonstrate, to the best of our knowledge, the first evidence for prodromal 5GABA-A receptor dysfunction in the AD hippocampal trisynaptic circuit. Moreover, as 5GABA-A receptors are located extrasynaptically and subserve the function of tonic inhibition we posit that an early stage of memory dysfunction involves the disruption of tonic inhibition in the hippocampus.