Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding.

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Learning and memory depend on activity-induced changes in dendritic translation.
• The specific mRNAs involved and their regulatory mechanisms remain largely unknown.

Purpose of the Study:

• To investigate how neuronal depolarization impacts local dendritic biology.
• To identify mRNAs and proteins regulated by neuronal activity in dendrites.

Main Methods:

• Dendritically targeted proximity labeling followed by crosslinking immunoprecipitation.
• Ribosome profiling and mass spectrometry were employed to analyze translational changes.
• Primary cortical neurons were depolarized using KCl or DHPG.

Main Results:

• Neuronal depolarization rapidly reprogrammed dendritic protein expression, with weak correlation between mRNA and protein changes.
• Depolarization enhanced translation of upstream open reading frames (uORFs) and downstream sequences for specific mRNAs.
• This process involved phosphorylation and recruitment of the translation initiation factor eIF4G2, enabling localized protein synthesis.

Conclusions:

• Activity-dependent translation of uORFs by eIF4G2 is a key mechanism coupling neuronal activity to local dendritic remodeling.
• This pathway regulates the production of proteins crucial for long-term potentiation, cell signaling, and energy metabolism.