Rab11 regulates autophagy at dendritic spines in an mTOR- and NMDA-dependent manner

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Synaptic plasticity is crucial for learning and memory, involving dynamic changes in neuronal connections.
• Autophagy, a cellular degradation process, is implicated in neurodevelopment and neurological disorders, with autophagosomes observed at dendritic spines during plasticity.
• The precise mechanisms initiating autophagosome formation at the postsynapse remain largely unknown.

Purpose of the Study:

• To elucidate the initial steps of autophagosome biogenesis at postsynaptic sites.
• To investigate the role of autophagy-related protein 9A (Atg9A) and Rab11 in activity-dependent autophagy at dendritic spines.

Main Methods:

• Postsynaptic association of Atg9A with Rab11 was examined.
• The impact of mTOR inhibition and NMDA receptor stimulation on Atg9A and LC3 localization was assessed.
• The effect of Rab11 dominant-negative (DN) overexpression on autophagosome formation was evaluated.

Main Results:

• Autophagy-related protein 9A (Atg9A) associates with Rab11 at dendritic spines, a process dependent on Rab11 activity.
• Inhibition of mTOR enhances the interaction between Rab11 and Atg9A, promoting LC3-positive vesicle formation at spines upon NMDA receptor stimulation.
• Newly formed autophagosomes (LC3+ vesicles) in dendritic spines confer resistance to NMDA-induced morphological changes, and Rab11 inhibition blocks their appearance.

Conclusions:

• Autophagosome initiation in dendritic spines is an activity-dependent process.
• The study identifies a novel Rab11a-dependent interaction of Atg9A, regulated by mTOR, as critical for initiating postsynaptic autophagy.
• This mechanism contributes to synaptic plasticity and spine stability.