Identification of cell-type-specific mRNA translational control mechanisms in synaptic plasticity and memory formation

The formation of long-term memories in the brain requires protein synthesis through mRNA translation. Newly synthesized proteins modify neural networks by strengthening or weakening synaptic connections through synapse alterations across numerous species. In rodents, both spatial and object recognition memory necessitate the activation of long-term depression at specific synapses in the hippocampus. The downstream pathway of long-term depression involves activating the eukaryotic initiation factor 2 (eIF2) pathway and protein synthesis. Phosphorylation of eIF2α plays a critical role in regulating the translation of specific mRNAs. Research indicates that the translation mediated by p-eIF2α is essential and sufficient for long-term depression and its associated learning behaviour. In contrast, blocking p-eIF2α prevents protein synthesis-dependent long-term depression. The cell type-specific cellular and molecular mechanisms by which p-eIF2α-dependent translation promotes synaptic plasticity and memory remain unknown. Different cell types in the brain have unique roles in shaping synaptic function, and identifying the cell-type-specific mechanisms involved in these processes explains how the brain adapts to its environments and experiences. We cross eIF2α knockout mice with inhibitory and excitatory Cre-recombinase-inducing mice by manipulating the expression of genes and signalling pathways. We then perform behavioural tests to investigate long-term depression in mice. The eIF2α knockout mice showed enhanced memories in excitatory Cre-recombinase-inducing mice, but no difference was observed in the inhibitory Cre-recombinase-inducing mice. This study aims to enhance our knowledge of molecular mechanisms of how the brain encodes new information and stores it as long-term memories, which has implications for understanding and treating memory-related disorders.