Activity disruption causes degeneration of entorhinal neurons in a mouse model of Alzheimer's circuit dysfunction
- Baylor College of Medicine, United States
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Joanna L Jankowsky
Funding
National Institute on Aging (RF1 AG058188)
- Joanna L Jankowsky
National Institute on Aging (RF1 AG058188-01S1)
- Joanna L Jankowsky
National Institute on Aging (R01 NS092615)
- Joanna L Jankowsky
Howard Hughes Medical Institute (GT13620)
- Joanna L Jankowsky
National Institute on Aging (F31 AG067676)
- Caleb A Wood
Alzheimer's Association (AARF-17-533487)
- Stacy D Grunke
BrightFocus Foundation (A2015016F)
- Stacy D Grunke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animals were handled and housed in accordance with recommendations in the NIH Guide for Care and Use of Laboratory Animals. All animal procedures were reviewed and approved by the BCM IACUC under protocol AN-4975.
Copyright
© 2022, Zhao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Activity disruption causes degeneration of entorhinal neurons in a mouse model of Alzheimer's circuit dysfunction
eLife 11:e83813.
https://doi.org/10.7554/eLife.83813
Further reading
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- Neuroscience
When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.
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- Neuroscience
When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
