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

Area of Science:

• Neuroscience
• Molecular Biology
• Behavioral Genetics

Background:

• mRNA translation regulation is crucial for brain development and function.
• Translation elongation factor 2 (eEF2) is a key regulator of protein synthesis and involved in cognitive functions.
• The role of eEF2 in specific brain regions and behaviors beyond the hippocampus remains largely unexplored.

Purpose of the Study:

• To investigate the role of eEF2 in regulating behaviors mediated by the prefrontal cortex.
• To determine if eEF2 deficiency in the medial prefrontal cortex (mPFC) affects social behavior and anxiety.
• To elucidate the molecular and synaptic mechanisms underlying eEF2-dependent behaviors.

Main Methods:

• Generation of Eef2 heterozygous (HET) mice with reduced eEF2 levels in excitatory neurons.
• Electrophysiological recordings to assess neuronal excitability and synaptic transmission in the mPFC.
• Behavioral tests including learning, memory, social interaction, and anxiety assays.
• Specific manipulation of eEF2 levels and neuronal activity in the mPFC.

Main Results:

• HET mice exhibited reduced eEF2 and protein synthesis in the mPFC excitatory neurons.
• These mice showed decreased spine density, reduced neuronal excitability, and impaired AMPA receptor-mediated synaptic transmission in the mPFC.
• While learning and memory were unaffected, HET mice displayed deficits in social behavior and increased anxiety.
• Specific knockdown of Eef2 in mPFC excitatory neurons impaired social novelty preference.
• Chemogenetic activation of mPFC neurons or AMPAR potentiation in the mPFC rescued the social novelty deficit.

Conclusions:

• eEF2 plays a critical role in regulating synaptic transmission in the medial prefrontal cortex.
• eEF2 is essential for normal social novelty behavior, likely through its modulation of AMPAR-mediated synaptic function.
• This study identifies a novel function for eEF2 in social cognition and anxiety, mediated by the prefrontal cortex.