Prodromal dysfunction of a5GABA-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 α5IA (an established memory enhancer and selective negative allosteric modulator of extrasynaptic tonically active α5GABA-A receptors) as a probe drug in TgF344-AD transgenic rats, a model for β-amyloid induced early onset AD. The results demonstrate that orally bioavailable α5IA 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 α5IA by 9 months of age, prior to the onset of AD-like pathology and memory dysfunction. TgF344-AD rats express human β-amyloid precursor protein (with the Swedish mutation) and human presenilin-1 (with a Δ exon 9 mutation) and we found high serum Aβ42 and Aβ40 levels by 3 months of age. When taken together, this demonstrates, to the best of our knowledge, the first evidence for prodromal α5GABA-A receptor dysfunction in the ripple-generating hippocampal trisynaptic circuit of AD-like transgenic rats. As α5GABA-A receptors are found at extrasynaptic and synaptic contacts, we posit that negative modulation of α5GABA-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. ; Published version