Autophagy is a lysosomal degradation pathway that regulates cellular homeostasis. It is constitutively active in neurons and controls the essential steps of neuronal development, leading to its dysfunction in neurodevelopmental disorders. Although mTOR-associated impaired autophagy has previously been reported in neurodevelopmental disorders, there is lack of information about the dysregulation of mTOR-independent autophagy in neurodevelopmental disorders. In this study, we investigated whether the loss of Epac2, involved in the mTOR-independent pathway, affects autophagy activity and whether the activity of autophagy is associated with social–behavioral phenotypes in mice with Epac2 deficiencies. We observed an accumulation of autophagosomes and a significant increase in autophagic flux in Epac2-deficient neurons, which had no effect on mTOR activity. Next, we examined whether an increase in autophagic activity contributed to the social behavior exhibited in Epac2−/− mice. The social recognition deficit observed in Epac2−/− mice recovered in double transgenic Epac2−/−: Atg5+/− mice. Our study suggests that excessive autophagy due to Epac2 deficiencies may contribute to social recognition defects through an mTOR-independent pathway.

中文翻译：

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自噬活动导致 Epac2-/- 小鼠的社会识别受损

自噬是调节细胞稳态的溶酶体降解途径。它在神经元中具有组成型活性并控制神经元发育的基本步骤，导致其在神经发育障碍中的功能障碍。尽管先前已在神经发育障碍中报道了与 mTOR 相关的受损自噬，但缺乏关于神经发育障碍中 mTOR 非依赖性自噬失调的信息。在这项研究中，我们调查了参与 mTOR 非依赖性途径的 Epac2 的缺失是否会影响自噬活性，以及​​自噬活性是否与 Epac2 缺陷小鼠的社会行为表型相关。我们观察到自噬体的积累和 Epac2 缺陷神经元中自噬通量的显着增加，这对 mTOR 活性没有影响。接下来，我们检查了自噬活动的增加是否有助于 Epac2-/- 小鼠表现出的社会行为。在 Epac2-/- 小鼠中观察到的社会识别缺陷在双转基因 Epac2-/-: Atg5+/- 小鼠中恢复。我们的研究表明，由于 Epac2 缺陷导致的过度自噬可能通过不依赖 mTOR 的途径导致社会识别缺陷。