Translational control and autism-like behaviors

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by social interaction deficits, communication impairments, and repetitive behaviors.
• Altered synaptic function and excitatory/inhibitory (E/I) balance are implicated in ASD pathogenesis.
• Eukaryotic initiation factor 4E (eIF4E)-dependent translation plays a role in regulating synaptic plasticity and neuronal function.

Purpose of the Study:

• To investigate the role of Eif4ebp2 deletion and subsequent increase in eIF4E-dependent protein synthesis in mouse models of ASD.
• To determine if modulating neuroligin (Nlgn) production and E/I balance can ameliorate autism-like behaviors.

Main Methods:

• Generated Eif4ebp2 knockout (Eif4ebp2^-/-) mice to increase eIF4E-dependent protein synthesis.
• Assessed social interaction, communication, and repetitive behaviors in Eif4ebp2^-/- mice.
• Measured E/I synaptic transmission in CA1 pyramidal neurons.
• Administered a cap-dependent translation inhibitor or used Nlgn1 knockdown.

Main Results:

• Eif4ebp2^-/- mice exhibited increased Nlgn production and an imbalanced E/I synaptic transmission.
• These molecular and synaptic alterations were associated with social deficits, communication impairments, and repetitive behaviors.
• Inhibition of cap-dependent translation or Nlgn1 knockdown restored E/I balance and reversed autism-like social deficits.

Conclusions:

• Increased eIF4E-dependent protein synthesis due to Eif4ebp2 deletion drives Nlgn production and synaptic E/I imbalance, contributing to autism-like phenotypes in mice.
• Targeting cap-dependent translation or Nlgn signaling represents a potential therapeutic strategy for reversing social deficits in ASD.