Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, by combining mouse models of neuron-specific ATG5 deficiency in either excitatory or inhibitory neurons with quantitative proteomics, high-content microscopy, and live-imaging approaches, we show that autophagy protein ATG5 functions in neurons to regulate cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA-R1, which sequesters the PKA catalytic subunit and diminishes cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins that mediate AMPAR trafficking. Furthermore, ATG5 deletion in glutamatergic neurons augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.

中文翻译：

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自噬通过控制突触处的 cAMP/蛋白激酶 A 信号来调节神经元兴奋性

自噬在饥饿期间提供营养并消除有害的细胞成分。然而，越来越多的证据表明自噬不仅仅是一个看家过程。在这里，通过将兴奋性或抑制性神经元中神经元特异性 ATG5 缺陷的小鼠模型与定量蛋白质组学、高内涵显微镜和活体成像方法相结合，我们表明自噬蛋白 ATG5 在神经元中发挥调节 cAMP 依赖性蛋白激酶 A 的作用(PKA)-介导的突触限制蛋白质组的磷酸化。ATG5 的这一功能与突触蛋白的大量周转无关，需要将 PKA 抑制性 R1 亚基靶向自噬体。ATG5 的神经元丢失导致 PKA-R1 的突触积累，它隔离 PKA 催化亚基并减少介导 AMPAR 运输的突触后细胞骨架蛋白的 cAMP/PKA 依赖性磷酸化。此外，谷氨酸能神经元中的 ATG5 缺失增强了 AMPAR 依赖性兴奋性神经传递，并导致小鼠出现自发性复发性癫痫发作。我们的研究结果确定了自噬在调节谷氨酸能突触 PKA 信号传导中的新作用，并表明 PKA 是自噬功能障碍的神经退行性疾病中恢复突触功能的目标。