Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum

Summary

Neurons are known to rely on autophagy for removal of defective proteins or organelles to maintain synaptic neurotransmission and counteract neurodegeneration. In spite of its importance for neuronal health, the physiological substrates of neuronal autophagy in the absence of proteotoxic challenge have remained largely elusive. We use knockout mice conditionally lacking the essential autophagy protein ATG5 and quantitative proteomics to demonstrate that loss of neuronal autophagy causes selective accumulation of tubular endoplasmic reticulum (ER) in axons, resulting in increased excitatory neurotransmission and compromised postnatal viability in vivo. The gain in excitatory neurotransmission is shown to be a consequence of elevated calcium release from ER stores via ryanodine receptors accumulated in axons and at presynaptic sites. We propose a model where neuronal autophagy controls axonal ER calcium stores to regulate neurotransmission in healthy neurons and in the brain.

Graphical Abstract

Highlights

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  Neuronal autophagy controls the endoplasmic reticulum (ER) in axons

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  Loss of neuronal autophagy leads to increased excitatory neurotransmission

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  Increased neurotransmission is due to elevated calcium release from ER stores

Abstract

Autophagy is crucial for nervous system function. However, its physiological substrates are largely unknown. Kuijpers et al. demonstrate, using knockout mice conditionally lacking the essential autophagy protein ATG5 and quantitative proteomics paired with electrophysiology and functional imaging experiments, that neuronal autophagy regulates presynaptic neurotransmission by controlling the axonal endoplasmic reticulum.