Early Hippocampal Sharp-Wave Ripple Deficits Predict Later Learning and Memory Impairments in an Alzheimer’s Disease Mouse Model

Abstract

Alzheimer's disease (AD) is characterized by progressive memory loss, and there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment.Hippocampal sharp-wave ripples (SWRs) -electrophysiological signatures of memory reactivation in the hippocampus -are a compelling candidate for doing so. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, but these alterations have yet to be directly linked to memory impairments. In aged apolipoprotein E4 knock in (apoE4-KI) mice -a model of the major genetic risk factor for AD -we found that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1-2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD.

Early and lifelong effects of APOE4 on neuronal gene expression networks relevant to Alzheimer’s disease

“…Gabra2, GABA A receptor alpha subunit, is involved in generation of brain oscillations critical for cognition 61 . We found a highly significant and consistent downregulation of Gabra2, which could link APOE4 to known oscillatory disruptions 62,63 . Thus, our results support prior studies that have documented synaptic deficits in APOE4-KI mouse brains 32,33,35 and, importantly, associate these detrimental effects to neuronal APOE4.…”

Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1

“…Article ll OPEN ACCESS SWR rate predicts memory impairments in Alzheimer's models (Jones et al, 2019). However, we found that suppressing SST + interneurons also lengthened SWRs, which may increase the length of the underlying replay trajectory, which could facilitate learning in some cases (Ferna ´ndez-Ruiz et al, 2019).…”

“…SST + interneurons in the DG are specifically lost in Alzheimer's disease and normal aging models, and the extent of their loss correlates with memory impairments (Andrews-Zwilling et al, 2010;Leung et al, 2012;Spiegel et al, 2013). These models show reduced SWR rate, frequency, and coincident SG power (Cayzac et al, 2015;Ciupek et al, 2015;Cowen et al, 2018;Gillespie et al, 2016;Iaccarino et al, 2016;Nicole et al, 2016;Wiegand et al, 2016), and the extent of these impairments predicts memory deficits (Jones et al, 2019). Suppression of DG and CA3 SST + interneurons induces similar changes in SWR characteristics, serving as further evidence that loss of these interneurons may be directly responsible for SWR alterations in pathological and normal aging and related memory deficits.…”

Impaired Hippocampal-Cortical Interactions during Sleep in a Mouse Model of Alzheimer’s Disease

“…In addition, mouse models of tauopathy and familial AD show changes in markers of memory replay. For example, the density and amplitude of hippocampal sharp wave ripples (SWRs) are reduced in these models [44][45][46][47].…”