eIF2α controls memory consolidation via excitatory and somatostatin neurons.

An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory ^1-4 . The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories ^5-10 . One of the most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins controlled by the translation initiation factor eIF2 ¹¹ . Phosphorylation of the α-subunit of eIF2 (p-eIF2α), the central component of the integrated stress response (ISR), impairs long-term memory formation in rodents and birds ^11-13 . By contrast, inhibiting the ISR by mutating the eIF2α phosphorylation site, genetically ¹¹ and pharmacologically inhibiting the ISR kinases ^14-17 , or mimicking reduced p-eIF2α with the ISR inhibitor ISRIB ¹¹ , enhances long-term memory in health and disease ¹⁸ . Here we used molecular genetics to dissect the neuronal circuits by which the ISR gates cognitive processing. We found that learning reduces eIF2α phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-eIF2α in either excitatory or somatostatin-expressing (but not parvalbumin-expressing) inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity and enhanced long-term memory. Thus, eIF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.