Autism-related deficits via dysregulated eIF4E-dependent translational control

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Autism spectrum disorders (ASDs) are linked to neuronal hyperconnectivity and increased synaptic protein synthesis.
• The mammalian target of rapamycin (mTOR) pathway is implicated in ASDs, but its downstream translational control mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), a downstream repressor of mTOR, in regulating synaptic function and autistic behaviors.
• To elucidate the translational control mechanisms of neuroligins, postsynaptic proteins associated with ASDs.

Main Methods:

• Generated knockout mice lacking the 4E-BP2 gene (Eif4ebp2).
• Examined the effects of 4E-BP2 knockout and eukaryotic translation initiation factor 4E (eIF4E) overexpression on neuroligin translation.
• Assessed synaptic excitation-to-inhibition ratios and autistic-like behaviors in mice.
• Utilized pharmacological inhibition of eIF4E and normalization of neuroligin protein levels.

Main Results:

• Loss of 4E-BP2 or overexpression of eIF4E increased neuroligin translation.
• Eif4ebp2 knockout mice displayed an elevated excitatory/inhibitory synaptic input ratio and autistic-like behaviors.
• Pharmacological inhibition of eIF4E or normalization of neuroligin 1 restored the excitation-inhibition balance and social behaviors.

Conclusions:

• Translational control mediated by eIF4E and its repressor 4E-BP2 is critical for regulating neuroligin synthesis.
• Dysregulation of this pathway disrupts the brain's excitation-inhibition balance, leading to ASD-like phenotypes.
• Targeting eIF4E activity or specific neuroligin levels may offer therapeutic strategies for ASDs.