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

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.

Automated summary

Neurons in the entorhinal cortex layer 2 (EC2) have been found to be unusually vulnerable to prolonged neuronal inactivity, and reelin + stellate cells connecting the EC and hippocampus are preferentially susceptible within the EC2 population. Multiple means of activity inhibition can lead to neuronal death, and preventing synaptic release is sufficient to induce silencing-induced degeneration. Furthermore, competition between active and inactive cells plays a role in the degeneration following synaptic silencing. This study suggests that the concept of a developmental window for lifelong circuit plasticity may extend into adulthood for specific brain regions.