Inhibition of the Integrated Stress Response Prevents Natural Forgetting and Corrects Accelerated Forgetting...

The neural mechanisms underlying the natural and maladaptive forgetting of established memory remain largely unknown. Brain disease states might hijack the physiological forgetting mechanisms, resulting in maladaptive forgetting such as accelerated forgetting that contributes to cognitive decline in various neurologic conditions including epilepsy. Based on the key role of the integrated stress response (ISR) in memory storage and maintenance, we determined whether the ISR underpins natural and accelerated forgetting. Here, based on the object location recognition (OLR) and novel object recognition (NOR) paradigms in mice, we found that the ISR was activated while an established memory was naturally forgotten, which was denoted by increased levels of phosphorylated eukaryotic translation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4), and reduced general protein synthesis. Multiple administrations of ISRIB, a small molecule ISR inhibitor, during the memory retention interval attenuated the ISR activation, and prevented the natural forgetting of established OLR and NOR memories. At the same time, a single injection of ISRIB has no effect on natural forgetting and memory retrieval. Moreover, administration of pentylenetetrazole (PTZ), an inducer of epileptic seizures, during the memory retention interval provoked the ISR activation and accelerated forgetting, which was corrected by ISRIB treatment. Together, our findings suggest that the ISR is critically involved in natural forgetting and accelerated forgetting associated with epilepsy, and pharmacological inhibition of the ISR may emerge as a novel intervention strategy for accelerated forgetting in patients with epilepsy.