TY - JOUR TI - Activity disruption causes degeneration of entorhinal neurons in a mouse model of Alzheimer’s circuit dysfunction AU - Zhao, Rong AU - Grunke, Stacy D AU - Wood, Caleb A AU - Perez, Gabriella A AU - Comstock, Melissa AU - Li, Ming-Hua AU - Singh, Anand K AU - Park, Kyung-Won AU - Jankowsky, Joanna L A2 - Slutsky, Inna A2 - Huguenard, John R A2 - Derdikman, Dori VL - 11 PY - 2022 DA - 2022/12/05 SP - e83813 C1 - eLife 2022;11:e83813 DO - 10.7554/eLife.83813 UR - https://doi.org/10.7554/eLife.83813 AB - 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. KW - selective vulnerability KW - entorhinal cortex KW - chemogenetic silencing KW - activity-dependent competition KW - circuit plasticity KW - Alzheimer's disease JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -