Prodromal dysfunction of α5GABA-A receptor modulated hippocampal ripples occurs prior to neurodegeneration in the TgF344-AD rat model of Alzheimer's disease

Decades of research attempting to slow the onset of Alzheimer's 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 alpha 5IA (an established memory enhancer and selective negative allosteric modulator of extrasynaptic tonically active alpha 5GABA-A receptors) as a probe drug in TgF344-AD transgenic rats, a model for beta-amyloid induced early onset AD. The results demonstrate that orally bioavailable alpha 5IA increases CA1 pyramidal cell mean firing rates during foraging and peak ripple amplitude during wakeful immobility in wild type F344 rats in a familiar environment. We further demonstrate that CA1 ripples in TgF344-AD rats are nonresponsive to alpha 5IA by 9 months of age, prior to the onset of AD-like pathology and memory dysfunction. TgF344-AD rats express human beta-amyloid precursor protein (with the Swedish mutation) and human presenilin-1 (with a Delta exon 9 mutation) and we found high serum A beta 42 and A beta 40 levels by 3 months of age. When taken together, this demonstrates, to the best of our knowledge, the first evidence for prodromal alpha 5GABA-A receptor dysfunction in the ripple-generating hippocampal trisynaptic circuit of AD-like transgenic rats. As alpha 5GABA-A receptors are found at extrasynaptic and synaptic contacts, we posit that negative modulation of alpha 5GABA-A receptor mediated tonic as well as phasic inhibition augments CA1 ripples and memory consolidation but that this modulatory mechanism is lost at an early stage of AD onset.