Autophagic vesicle content profiling from hippocampal slices LC-MSMS

Previous work demonstrated that the developmental pruning of dendritic spines requires autophagy. This developmental process is facilitated by long-term depression (LTD)-like mechanisms, inviting the speculation that LTD, a fundamental form of plasticity, itself requires autophagy. Here, we show that LTD-inducing activation of NMDA receptors or metabotropic glutamate receptors triggers the rapid initiation of autophagy in postsynaptic dendrites. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPAR subunits from the surface and rapidly degrade them and their scaffold PSD95. Moreover, during NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. In turn, pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and instead triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression.