Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology

Tal Nuriel, Sergio L. Angulo, Usman Khan, Archana Ashok, Qiuying Chen, Helen Y. Figueroa, Sheina Emrani, Li Liu, Mathieu Herman, Geoffrey Barrett, Valerie Savage, Luna Buitrago, Efrain Cepeda-Prado, Christine Fung, Eliana Goldberg, Steven S. Gross, S. Abid Hussaini, Herman Moreno (), Scott A. Small () and Karen E. Duff ()
Additional contact information
Tal Nuriel: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Sergio L. Angulo: The Robert F. Furchgott Center for Neural and Behavioral Science
Usman Khan: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Archana Ashok: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Qiuying Chen: Weill Cornell Medical College
Helen Y. Figueroa: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Sheina Emrani: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Li Liu: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Mathieu Herman: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Geoffrey Barrett: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Valerie Savage: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Luna Buitrago: The Robert F. Furchgott Center for Neural and Behavioral Science
Efrain Cepeda-Prado: The Robert F. Furchgott Center for Neural and Behavioral Science
Christine Fung: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Eliana Goldberg: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Steven S. Gross: Weill Cornell Medical College
S. Abid Hussaini: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Herman Moreno: The Robert F. Furchgott Center for Neural and Behavioral Science
Scott A. Small: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Karen E. Duff: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques—fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics—with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.

Date: 2017
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DOI: 10.1038/s41467-017-01444-0

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