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

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

Author information

  • 1Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA.
  • 2Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA; Neuroscience 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.
  • 4Kavli 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.
  • 5Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA.
  • 6Gladstone 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.
  • 7Neuroscience 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.
  • 8Gladstone 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.

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.

PMID:
27161522
PMCID:
PMC5097044
[Available on 2017-05-18]
DOI:
10.1016/j.neuron.2016.04.009
[PubMed - in process]
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