Behavioral Neural Circuitry and Physiology Laboratory, Department of Anatomy, Brain Science and Engineering Institute, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.
Department of Biological Sciences and Biotechnology, College of Life Sciences and Nanotechnology, Hannam University, Daejeon, South Korea.
Mol Brain. 2021 Jun 28;14(1):100. doi: 10.1186/s13041-021-00814-6.
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.
自噬是一种溶酶体降解途径，可调节细胞内稳态。它在神经元中持续活跃，并控制神经元发育的基本步骤，导致其在神经发育障碍中功能失调。尽管先前在神经发育障碍中报道了与 mTOR 相关的自噬受损，但关于神经发育障碍中 mTOR 非依赖性自噬的失调信息却缺乏。在这项研究中，我们研究了参与 mTOR 非依赖性途径的 Epac2 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 Epac2 缺陷神经元中自噬体的积累和自噬流的显著增加，而这对 mTOR 活性没有影响。接下来，我们研究了自噬活性的增加是否有助于 Epac2 小鼠表现出的社会行为。在 Epac2 小鼠中观察到的社交识别缺陷在 Epac2:Atg5 双转基因小鼠中得到恢复。我们的研究表明，由于 Epac2 缺陷导致的过度自噬可能通过 mTOR 非依赖性途径导致社交识别缺陷。
