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.

众所周知，神经元依赖自噬来去除有缺陷的蛋白质或细胞器，以维持突触神经传递和对抗神经退行性变。尽管它对神经元健康很重要，但在没有蛋白质毒性挑战的情况下，神经元自噬的生理底物在很大程度上仍然难以捉摸。我们使用条件性缺乏必需自噬蛋白 ATG5 和定量蛋白质组学的敲除小鼠来证明神经元自噬的丧失导致轴突中管状内质网 (ER) 的选择性积累，从而导致兴奋性神经传递增加和出生后体内活力受损. 兴奋性神经传递的增加被证明是通过在轴突和突触前部位积累的兰尼碱受体从 ER 储存中释放钙升高的结果。我们提出了一个模型，其中神经元自噬控制轴突 ER 钙储存以调节健康神经元和大脑中的神经传递。