eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior

Abstract

Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus‐dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has been unknown. Here, we construct a line of Eef2 heterozygous (HET) mice, which show a reduction in eEF2 and protein synthesis mainly in excitatory neurons of the prefrontal cortex. The mice also show lower spine density, reduced excitability, and AMPAR‐mediated synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC). While HET mice exhibit normal learning and memory, they show defective social behavior and elevated anxiety. Knockdown of Eef2 in excitatory neurons of the mPFC specifically is sufficient to impair social novelty preference. Either chemogenetic activation of excitatory neurons in the mPFC or mPFC local infusion of the AMPAR potentiator PF‐4778574 corrects the social novelty deficit of HET mice. Collectively, we identify a novel role for eEF2 in promoting prefrontal AMPAR‐mediated synaptic transmission underlying social novelty behavior. image Translation elongation factor eEF2 maintains de novo synthesis of proteins including GluA2 in excitatory neurons of the medial prefrontal cortex, thus promoting AMPAR‐mediated excitatory synaptic transmission for normal social novelty behavior. Insufficient eEF2 in the mPFC results in decreased protein synthesis in excitatory neurons and fewer excitatory synapses. eEF2 maintains GluA2‐containing AMPAR levels at the synapse, thus promoting AMPAR‐mediated synaptic transmission. Both Eef2 HET mice and mice with Eef2 knockdown specifically in mPFC excitatory neurons exhibit social novelty deficit. Restoration of excitability in mPFC pyramidal neurons and pharmacological activation of AMPAR in mPFC rescue social novelty deficits in Eef2 HET mice.