Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples

• Published in: Neuron (Cambridge, Mass.) Vol. 90; no. 4; pp. 740 - 751
• Main Authors: Gillespie, Anna K., Jones, Emily A., Lin, Yuan-Hung, Karlsson, Mattias P., Kay, Kenneth, Yoon, Seo Yeon, Tong, Leslie M., Nova, Philip, Carr, Jessie S., Frank, Loren M., Huang, Yadong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-05-2016; Elsevier Limited
• Subjects: Age; Aging; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apolipoprotein E4 - genetics; Apolipoprotein E4 - metabolism; Apolipoproteins; Cognition Disorders - genetics; Cognition Disorders - metabolism; Disease Models, Animal; Gene Knock-In Techniques - methods; Hippocampus - metabolism; Interneurons - metabolism; Maze Learning - physiology; Memory; Memory Disorders - genetics; Memory Disorders - metabolism; Mice, Transgenic; Mortality; Pathology; Rodents; Studies
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2016.04.009

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD), but the mechanism by which it causes cognitive decline is unclear. In knockin (KI) mice, human apoE4 causes age-dependent learning and memory impairments and degeneration of GABAergic interneurons in the hippocampal dentate gyrus. Here we report two functional apoE4-KI phenotypes involving sharp-wave ripples (SWRs), hippocampal network events critical for memory processes. Aged apoE4-KI mice had fewer SWRs than apoE3-KI mice and significantly reduced slow gamma activity during SWRs. Elimination of apoE4 in GABAergic interneurons, which prevents learning and memory impairments, rescued SWR-associated slow gamma activity but not SWR abundance in aged mice. SWR abundance was reduced similarly in young and aged apoE4-KI mice; however, the full SWR-associated slow gamma deficit emerged only in aged apoE4-KI mice. These results suggest that progressive decline of interneuron-enabled slow gamma activity during SWRs critically contributes to apoE4-mediated learning and memory impairments.
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•ApoE4-KI mice show age-dependent attenuation of slow gamma activity during SWRs•ApoE4-KI mice, both young and aged, have fewer SWRs than apoE3-KI mice•ApoE4-induced slow gamma impairment, not SWR abundance, is interneuron dependent•Progressive slow gamma dysfunction during SWRs may contribute to cognitive decline
Gillespie et al. show that Alzheimer’s disease risk factor apoE4 alters hippocampal sharp-wave ripples (SWRs), network events important for memory function. In particular, dysfunction of SWR-associated slow gamma activity may critically contribute to apoE4-induced learning and memory impairment.