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We investigated how persistent ISR activation affects cognitive performance by studying the PPP1R15B\n                    <jats:sup>R658C<\/jats:sup>\n                    genetic variant associated with intellectual disability. To model this condition, we generated a mouse line with the pathogenic allele inserted. This variant destabilized the PPP1R15B\u2022PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. We demonstrated that the cognitive and synaptic impairments in\n                    <jats:italic toggle=\"yes\">Ppp1r15b<\/jats:italic>\n                    <jats:sup>R658C<\/jats:sup>\n                    mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral ortholog of PPP1R15B, which acted as a potent pan-ISR inhibitor. 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