Activity disruption causes degeneration of entorhinal neurons in a mouse model of Alzheimer’s circuit dysfunction

Author:

Zhao Rong1,Grunke Stacy D1,Wood Caleb A1ORCID,Perez Gabriella A1,Comstock Melissa1,Li Ming-Hua1,Singh Anand K1,Park Kyung-Won1,Jankowsky Joanna L12ORCID

Affiliation:

1. Department of Neuroscience, Huffington Center on Aging, Baylor College of Medicine

2. Departments of Neurology, Neurosurgery, and Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine

Abstract

Neurodegenerative diseases are characterized by selective vulnerability of distinct cell populations; however, the cause for this specificity remains elusive. Here, we show that entorhinal cortex layer 2 (EC2) neurons are unusually vulnerable to prolonged neuronal inactivity compared with neighboring regions of the temporal lobe, and that reelin + stellate cells connecting EC with the hippocampus are preferentially susceptible within the EC2 population. We demonstrate that neuronal death after silencing can be elicited through multiple independent means of activity inhibition, and that preventing synaptic release, either alone or in combination with electrical shunting, is sufficient to elicit silencing-induced degeneration. Finally, we discovered that degeneration following synaptic silencing is governed by competition between active and inactive cells, which is a circuit refinement process traditionally thought to end early in postnatal life. Our data suggests that the developmental window for wholesale circuit plasticity may extend into adulthood for specific brain regions. We speculate that this sustained potential for remodeling by entorhinal neurons may support lifelong memory but renders them vulnerable to prolonged activity changes in disease.

Funder

National Institute on Aging

Howard Hughes Medical Institute

Alzheimer's Association

BrightFocus Foundation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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