School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
Int J Mol Sci. 2022 Aug 17;23(16):9228. doi: 10.3390/ijms23169228.
The beneficial effects of diet and exercise on brain function are traditionally attributed to the enhancement of autophagy, which plays a key role in neuroprotection via the degradation of potentially harmful intracellular structures. The molecular machinery of autophagy has also been suggested to influence synaptic signaling via interaction with trafficking and endocytosis of synaptic vesicles and proteins. Still, the role of autophagy in the regulation of synaptic plasticity remains elusive, especially in the mammalian brain. We explored the impact of autophagy on synaptic transmission and homeostatic and acute synaptic plasticity using transgenic mice with induced deletion of the Beclin1 protein. We observed down-regulation of glutamatergic and up-regulation of GABAergic synaptic currents and impairment of long-term plasticity in the neocortex and hippocampus of Beclin1-deficient mice. Beclin1 deficiency also significantly reduced the effects of environmental enrichment, caloric restriction and its pharmacological mimetics (metformin and resveratrol) on synaptic transmission and plasticity. Taken together, our data strongly support the importance of autophagy in the regulation of excitatory and inhibitory synaptic transmission and synaptic plasticity in the neocortex and hippocampus. Our results also strongly suggest that the positive modulatory actions of metformin and resveratrol in acute and homeostatic synaptic plasticity, and therefore their beneficial effects on brain function, occur via the modulation of autophagy.
饮食和运动对大脑功能的有益影响传统上归因于自噬的增强，自噬通过降解潜在有害的细胞内结构在神经保护中发挥关键作用。自噬的分子机制也被认为通过与突触囊泡和蛋白质的运输和内吞作用相互作用来影响突触信号转导。尽管如此，自噬在调节突触可塑性中的作用仍然难以捉摸，尤其是在哺乳动物大脑中。我们使用诱导 Beclin1 蛋白缺失的转基因小鼠，探讨了自噬对突触传递以及稳态和急性突触可塑性的影响。我们观察到 Beclin1 缺陷型小鼠的谷氨酸能突触电流下调和 GABA 能突触电流上调，以及长时程可塑性受损。Beclin1 缺乏还显著降低了环境富集、热量限制及其药理学模拟物（二甲双胍和白藜芦醇）对突触传递和可塑性的影响。总之，我们的数据强烈支持自噬在调节新皮层和海马中的兴奋性和抑制性突触传递和突触可塑性中的重要性。我们的结果还强烈表明，二甲双胍和白藜芦醇在急性和稳态突触可塑性中的正调节作用，以及它们对大脑功能的有益影响，是通过自噬的调节而发生的。
