title: Apolipoprotein E4 Causes Age-Dependent Disruption of Slow Gamma Oscillations during Hippocampal Sharp-Wave Ripples.
abstract: 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. VIDEO ABSTRACT.
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Gillespie
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Jones
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, CA 94143, USA.
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Kavli Institute for Fundamental Neuroscience and Department of Physiology, University of California, San Francisco, CA 94158, USA.
authors.forename: Mattias P
authors.initials: MP
authors.lastname: Karlsson
authors.affiliation: Kavli Institute for Fundamental Neuroscience and Department of Physiology, University of California, San Francisco, CA 94158, USA; Bioengineering Graduate Program, University of California, San Francisco, CA 94143, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kay
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Seo Yeon
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Tong
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Nova
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, CA 94143, USA.
authors.forename: Jessie S
authors.initials: JS
authors.lastname: Carr
authors.affiliation: Neuroscience Graduate Program, University of California, San Francisco, CA 94143, USA; Kavli Institute for Fundamental Neuroscience and Department of Physiology, University of California, San Francisco, CA 94158, USA; Bioengineering Graduate Program, University of California, San Francisco, CA 94143, USA.
authors.forename: Loren M
authors.initials: LM
authors.lastname: Frank
authors.affiliation: Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, CA 94143, USA; Departments of Neurology and Pathology, University of California, San Francisco, CA 94143, USA. Electronic address: yadong.huang@gladstone.ucsf.edu.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques / Q000379:methods; D006624:Hippocampus / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic
chemical_list: D053327:Apolipoprotein E4