Grant: Discovery Grants Program - Individual

The formation of long-term memories in the brain requires de novo protein synthesis through mRNA translation. The spatial and object recognition memory requires the activation of group-I metabotropic glutamate receptors (mGluRs) and long-term depression (LTD) at specific synapses in the hippocampus. The downstream pathway of mGluRI-dependent LTD needs the activation of the eukaryotic initiation factor 2 (eIF2) pathway to initiate translation. The phosphorylation of eIF2a plays a crucial role in regulating the translation of specific mRNAs. Four eIF2a kinases (HRI, PKR, GCN2, and PERK) phosphorylate eIF2a at serine-51, which leads to a decrease in the ternary complex, facilitating the translation of selective mRNAs required for synaptic modification and memory formation. The pharmacological induction of mGluR-LTD rapidly increases eIF2a phosphorylation (p-eIF2a) and the translation of transcription factors called "LTD proteins." Research indicates that the translation mediated by p-eIF2a is essential and sufficient for mGluR-LTD and its associated learning behavior. In contrast, blocking p-eIF2a by mutating the eIF2a phosphorylation site and genetically and pharmacologically inhibiting the eIF2a kinases prevents protein synthesis-dependent mGluR-LTD. However, the cell type-specific cellular and molecular mechanisms by which p-eIF2a-dependent translation promotes synaptic plasticity and memory remain unknown. Therefore, this research will utilize unique mouse models and viral vectors expressing Cre-recombinase under cell-type-specific promoters. By combining these targeted approaches with advanced tools like RNA interference (RNAi), chemogenetics, and unique transgenic mouse models, our research group will uncover the mechanism through which the two essential cell types, excitatory and inhibitory neurons, orchestrate mGluR-LTD and p-eIF2a-dependent protein creation during synaptic plasticity and memory formation. Specific Aims Studies should focus on measuring de novo protein synthesis and identifying differentially translated mRNAs in excitatory and inhibitory neurons during various stages of memory formation. Our ultimate goal is to understand how the p-eIF2a pathway regulates fundamental brain processes specific to certain cell types and how this impacts synaptic adaptation, learning, and memory. Short-term goal: To identify the subsets of neurons in which p-eIF2a-dependent de novo protein synthesis is required for LTD and memory. We have the following three aims: Aim 1. Investigate the mGluR-dependent activation of eIF2a-kinases and downstream eIF2a phosphorylation activity in excitatory and inhibitory neurons. Aim 2. Determine the effect of p-eIF2a signaling on synaptic development and neuronal circuit formation and function. Aim 3.Studying the mechanism by which the translation of p-eIF2a-sensitive mRNAs and newly synthesized proteins controls synaptic plasticity and memory.