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

Abstract

Synaptic plasticity is a process that shapes neuronal connections during neurodevelopment, learning, and memory. Autophagy is a mechanism that allows cells to degrade their unnecessary or dysfunctional components. Autophagosomes appear at dendritic spines in response to plasticity-inducing stimuli. Autophagy defects contribute to altered dendritic spine development, autistic-like behavior in mice, and neurological disease. While several studies explored the involvement of autophagy in synaptic plasticity, the steps preceding autophagosome emergence at the postsynapse remain unknown. Here we show a postsynaptic association of autophagy-related protein 9A (Atg9A), known to be involved in the initial stages of autophagosome formation, with Rab11, a small GTPase that regulates endosomal trafficking. Rab11 activity is necessary for the maintenance of Atg9A-positive structures at dendritic spines. Inhibition of mTOR increased Rab11 and Atg9A interaction and increased the emergence of autophagosomes in dendritic spines when coupled to NMDA receptor stimulation. Dendritic spines with newly formed autophagosomes were more resistant to NMDA-induced morphologic change. These results collectively suggest that autophagy initiation in dendritic spines depends on an activity-dependent Rab11a-Atg9A interaction regulated by mTOR.