Apolipoprotein E4-induced Hippocampal Network Activity Deficits Correlate with Learning and Memory Impairments Emily Jones1,2, Anna Gillespie3, Seo Yeon Yoon1, Loren Frank3, Yadong Huang1,2,4 1Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; 2Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA; 3Kavli Institute for Fundamental Neuroscience and Department of Physiology, University of California, San Francisco, CA 94158, USA; 4Departments of Neurology and Pathology, University of California, San Francisco, CA 94143, USA
Alzheimer's disease is characterized by progressive cognitive decline, yet our ability to measure disease progression at functional level in animal models is limited. To address this, we built upon our previous finding that aged female apoE4 knock in (KI) mice show deficits in two hippocampal network signatures of learning and memory: reduced abundance of sharp wave ripples (SWR), the local field potential signature of place cell replay which are critical for memory consolidation, and reduced SWR-associated slow gamma power, which coordinates this replay across regions and hemispheres. We investigated whether these network deficits correlate with spatial learning and memory deficits. We found that the SWR abundance correlates with learning early in water maze in apoE4-KI mice, while SWR-associated slow gamma power correlates with memory during probe trials in apoE4-KI mice. We then measured progression of these network phenotypes by recording from mice every 3 months over aging and determined how well they predicted future learning and memory impairment. We determined that the onset of SWR-associated slow gamma power loss correlates with the onset of GABAergic interneuron loss, and that this slow gamma power loss at early ages could predict memory impairment at later ages. These results provide evidence that SWR-associated slow gamma power could be used as a functional biomarker at the network-level to monitor in mouse models the progression of AD symptoms over aging or the success of therapeutic interventions.
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