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

Anna K Gillespie; Emily A Jones; Yuan-Hung Lin; Mattias P Karlsson; Kenneth Kay; Seo Yeon Yoon; Leslie M Tong; Philip Nova; Jessie S Carr; Loren M Frank; Yadong Huang

doi:10.1016/j.neuron.2016.04.009

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

Neuron. 2016 May 18;90(4):740-51. doi: 10.1016/j.neuron.2016.04.009. Epub 2016 May 5.

Authors

Affiliations

¹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
² Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience Graduate Program, University of California, San Francisco, CA 94143, USA.
³ Kavli Institute for Fundamental Neuroscience and Department of Physiology, University of California, San Francisco, CA 94158, USA.
⁴ 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.
⁵ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
⁶ 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.
⁷ 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.
⁸ 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging
Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Animals
Apolipoprotein E4 / genetics
Apolipoprotein E4 / metabolism*
Cognition Disorders / genetics
Cognition Disorders / metabolism*
Disease Models, Animal
Gene Knock-In Techniques / methods
Hippocampus / metabolism*
Interneurons / metabolism*
Maze Learning / physiology
Memory Disorders / genetics
Memory Disorders / metabolism*
Mice, Transgenic

Substances

Apolipoprotein E4

Abstract

Publication types

MeSH terms

Substances

Grants and funding