Long-term synaptic depression triggers local biogenesis of autophagic vesicles in dendrites and requires autophagic degradation

Kallergi, E.; Daskalaki, A. D.; Ioannou, E.; Kolaxi, A.; Plataki, M.; Haberkant, P.; Stein, F.; Savitski, M. M.; Sidiropoulou, K.; Dalezios, Y.; Nikoletopoulou, V.

doi:10.1101/2020.03.12.983965

bioRxiv · 10.1101/2020.03.12.983965

Long-term synaptic depression triggers local biogenesis of autophagic vesicles in dendrites and requires autophagic degradation

Kallergi, E.·Daskalaki, A. D.·Ioannou, E.·Kolaxi, A.·Plataki, M.·Haberkant, P.·Stein, F.·Savitski, M. M.·Sidiropoulou, K.·Dalezios, Y.·Nikoletopoulou, V.

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Abstract

In neurons, biogenesis of autophagic vesicles (AVs) is spatially confined to the axon tip under baseline conditions. However, it remains unknown whether their biogenesis can be induced in other neuronal compartments following synaptic activity in order to serve local functions. Here, we show that both major types of long-term synaptic depression (LTD), a form of plasticity expressed by the shrinkage and elimination of dendritic spines, trigger the rapid and local biogenesis of AVs in post-synaptic dendrites. In return, autophagy is indispensable for LTD, as either genetic ablation of atg5 in pyramidal neurons or acute pharmacological inhibition of AV biogenesis totally prevents LTD induction. Using quantitative proteomic profiling of purified AVs, we reveal that upon LTD the autophagic cargo is significantly enriched for synaptic proteins, as well as modulators of the actin cytoskeleton and autism-implicated proteins. In line with these findings, a mild autophagy deficit is sufficient to impair behavioral flexibility, a cognitive function that requires efficient LTD. Therefore, local synthesis and assembly of the autophagic machinery in dendrites ensure the elimination of synaptic structures via degradation of their components, facilitating plasticity and associated behaviors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=165 HEIGHT=200 SRC="FIGDIR/small/983965v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1a7bc14org.highwire.dtl.DTLVardef@12cece0org.highwire.dtl.DTLVardef@738687org.highwire.dtl.DTLVardef@8518af_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefKallergi, Daskalaki and colleagues demonstrate that autophagy is cell autonomously required in pyramidal excitatory neurons for the induction of long-term synaptic depression (LTD). They uncover the novel and local biogenesis of autophagic vesicles (AVs) in dendrites upon LTD, by which post-synaptic components are rapidly accessible on-site for autophagic degradation. Using quantitative proteomics on purified AVs, they reveal that upon LTD the autophagic cargo is enriched in synaptic, cytoskeletal and autism-implicated proteins. HighlightsO_LIAutophagy is required cell-autonomously in pyramidal neurons for LTD. C_LIO_LINMDAR- and mGluR-mediated LTD trigger the local biogenesis of autophagic vesicles in dendrites. C_LIO_LIAutophagic vesicles sequester primarily synaptic and cytoskeletal cargo upon LTD. C_LIO_LIMild impairment in autophagy leads to deficits in cognitive flexibility. C_LI

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Kallergi, E., Daskalaki, A. D., Ioannou, E., Kolaxi, A., Plataki, M., Haberkant, P., Stein, F., Savitski, M. M., Sidiropoulou, K., Dalezios, Y., Nikoletopoulou, V.. 2020-03-13. Long-term synaptic depression triggers local biogenesis of autophagic vesicles in dendrites and requires autophagic degradation. https://doi.org/10.1101/2020.03.12.983965

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