Cell-Type-Specific Regulation of the eIF2α Pathway in Long-Term Memory

Long-term memory consolidation results from synaptic plasticity dependent on mRNA translation. One of the translation mechanisms is regulated by eukaryotic translation initiation factor 2 alpha (eIF2α). The phosphorylation of eIF2α leads to a decrease in general translation while inducing the translation of specific mRNA transcripts. While the regulation of protein synthesis through the eIF2α pathway has been shown to influence long-term potentiation, its role in long-term depression (LTD) remains much less explored. Research suggests that phosphorylated eIF2α (p-eIF2α) regulation is cell-type-specific, however this research has focused primarily on long-term potentiation, not LTD. We hypothesize that p-eIF2α levels are differentially regulated across specific cell types during LTD. To investigate this, we will use novel object recognition, a long-term memory task, to induce LTD in mice. Immunohistochemistry will be performed to visualize p-eIF2α and total eIF2α expression across various hippocampal cell types, including excitatory neurons, inhibitory neurons, parvalbumin-expressing interneurons, somatostatin interneurons, astrocytes, vasoactive intestinal peptide-expressing interneurons, and microglia. The kinases regulating p-eIF2α expression (PKR, PERK, GCN2, and MARK) will then be assessed to determine which are upregulated. We expect to identify specific cell types expressing increased p-eIF2α levels following LTD induction, providing insight into cell-type-specific regulation of the eIF2α pathway. Proper regulation of the eIF2α signalling pathway is crucial for synaptic plasticity and memory. Consequently, chronic activation of p-eIF2α is linked to various neurological disorders, highlighting its potential as a therapeutic target and the significance of our research for future health advancements.