Neuronal Autophagy Regulates Presynaptic Neurotransmission by Controlling the Axonal Endoplasmic Reticulum

Neuron. 2021 Jan 20;109(2):299-313.e9. doi: 10.1016/j.neuron.2020.10.005. | PubMed

Marijn Kuijpers¹, Gaga Kochlamazashvili¹, Alexander Stumpf², Dmytro Puchkov¹, Aarti Swaminathan², Max Thomas Lucht¹, Eberhard Krause¹, Tanja Maritzen¹, Dietmar Schmitz², Volker Haucke³

1. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
2. Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
3. Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany; Freie Universität Berlin, Faculty of Biology, Chemistry, and Pharmacy, 14195 Berlin, Germany. Electronic address: haucke@fmp-berlin.de.

Abstract

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.

Presented By Marijn Kuijpers | ORCID iD