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.

Expansion of clinical and variant spectrum of EEF2‐related neurodevelopmental disorder: Report of two additional cases

“…Although eEF2 is a ubiquitously expressed protein involved in protein translation regulation, clinical symptoms of EEF2 ‐related neurodevelopmental disorder and EEF2 ‐related SCA indicate the particular importance of eEF2 in neuronal function. This observation comports with basic research findings suggesting the importance of eEF2 in regulating neurogenesis, synaptic function and social novelty behavior (Ma et al, 2022; Taha et al, 2020). EEF2 ‐related disorder serves as a valuable model to understand the role of eEF2 in regulating neurocognitive development in human.…”

“…Our data suggest that not only specific missense variants, but also loss‐of‐function variants cause EEF2 ‐related neurodevelopmental disorder. In the previous study evaluating the neurobehavioral phenotype of heterozygous loss‐of‐function Eef2 mutant mice, alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid receptor (AMPAR) potentiator, PF‐4778574, corrected neurobehavioral phenotype of these mice (Ma et al, 2022). Our demonstration that EEF2 loss‐of‐function variants cause a neurodevelopmental phenotype in human, raising an interesting possibility that AMPAR potentiator may also ameliorate neurological symptoms of human patients with EEF2 ‐related neurodevelopmental disorder.…”

Translational patterns of ionotropic glutamate and GABA receptors during brain development and behavioral stimuli revealed by polysome profiling

“…N2518) for the dissection of the cerebral cortex, prefrontal cortex, and hippocampus. To obtain the prefrontal cortex, the olfactory bulb was removed first, and the slice containing the frontal part of the brain with, two‐millimeters thin, was dissected out (Ma et al, 2022). All tissues were snap‐frozen in liquid nitrogen and stored at −80°C.…”

Magnetically Manipulated Optoelectronic Hybrid Microrobots for Optically Targeted Non‐Genetic Neuromodulation

“…Primary hippocampal neurons were cultured in two coverslips, separately placed in wells, and cultured for 14 days. [50,53] MOHR swarms were injected into the middle of the channel to simulate the real biological environment, followed by controlled movement toward the right well (Figure 6f-h). The total traveling distance was estimated to be over 10 mm (Movie S14, Supporting Information).…”