Abstract
Seizures can induce endoplasmic reticulum (ER) stress, and sustained ER stress contributes to neuronal death after epileptic seizures. Despite the recent debate on whether inhibiting ER stress can reduce neuronal death after seizures, whether and how ER stress impacts neural activity and seizures remain unclear. In this study, we discovered that the acute ER stress response functions to repress neural activity through a protein translation-dependent mechanism. We found that inducing ER stress promotes the expression and distribution of murine double minute-2 (Mdm2) in the nucleus, leading to ubiquitination and down-regulation of the tumor suppressor p53. Reduction of p53 subsequently maintains protein translation, before the onset of translational repression seen during the latter phase of the ER stress response. Disruption of Mdm2 in an Mdm2 conditional knockdown (cKD) mouse model impairs ER stress-induced p53 down-regulation, protein translation, and reduction of neural activity and seizure severity. Importantly, these defects in Mdm2 cKD mice were restored by both pharmacological and genetic inhibition of p53 to mimic the inactivation of p53 seen during ER stress. Altogether, our study uncovered a novel mechanism by which neurons respond to acute ER stress. Further, this mechanism plays a beneficial role in reducing neural activity and seizure severity. These findings caution against inhibition of ER stress as a neuroprotective strategy for seizures, epilepsies, and other pathological conditions associated with excessive neural activity.
Highlights
A seizure is an uncontrolled electrical disturbance in the brain
Our study provides evidence to demonstrate a novel and beneficial role for the endoplasmic reticulum (ER) stress response in reducing neural activity and seizure severity
To determine whether and how acute ER stress modulates protein translation, we studied murine double minute-2 (Mdm2), a ubiquitin E3 ligase known to participate in various cellular stress responses [35, 36]
Summary
A seizure is an uncontrolled electrical disturbance in the brain. Recurrent and spontaneous seizures lead to epilepsy, a pathological condition affecting 50 million people worldwide. Among the cellular mechanisms that contribute to excitotoxicity-induced cell damage, endoplasmic reticulum (ER) stress has gained much attention [7, 8]. ER stress has been observed and suggested to contribute to cell death in various brain regions after chronic seizures or epilepsies [5], a recent study has proposed that ER stress can be crucial for neuronal survival after seizures [3]. Despite this controversy, it remains unknown whether and how the ER stress response might affect or modulate the hyperexcitability that occurs during seizure onset
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