Morishita Misaki, Matsuda Shinji
Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, Tokyo 182-8585, Japan.
Department of Engineering Science, Graduate School of Informatics and Engineering, The University of Electro-Communications, Tokyo 182-8585, Japan; Center for Neuroscience and Biomedical Engineering (CNBE), The University of Electro-Communications, Tokyo 182-8585, Japan.
Neurosci Res. 2025 Jan;210:28-37. doi: 10.1016/j.neures.2024.09.005. Epub 2024 Sep 28.
Long-term depression (LTD) is a form of synaptic plasticity thought to be the cellular basis of experience-dependent learning and memory. LTD is caused by an activity-dependent decrease in cell surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPA receptors) at the postsynaptic sites. However, the mechanism through which AMPA receptors are removed from the cell surface via neuronal activity is not fully understood. In this study, we showed that small interfering RNA (siRNA)-mediated knockdown of sterile alpha and toll/interleukin receptor motif containing 1 (SARM1) in cultured hippocampal neurons prevented the N-methyl-d-aspartate (NMDA)-induced reduction in cell surface AMPA receptors. However, the control RNA did not affect NMDA-mediated AMPA receptor trafficking. Overexpression of the siRNA-resistant form of SARM1 in SARM1-knocked-down neurons restored AMPA receptor trafficking. However, overexpression of SARM1, which lacks the mitochondrial transport signal, in the SARM1-knocked-down neurons did not restore NMDA-dependent AMPA receptor endocytosis. Moreover, the inhibition of the NADase activity of SARM1 blocked the NMDA-induced reduction of cell surface AMPA receptors. These results suggest that both the mitochondrial localization and NADase activity of SARM1 are essential for NMDA receptor-dependent AMPA receptor internalization in the hippocampal neurons.
长期抑郁（LTD）是一种突触可塑性形式，被认为是经验依赖性学习和记忆的细胞基础。LTD是由突触后位点细胞表面α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体（AMPA受体）的活性依赖性减少引起的。然而，通过神经元活动将AMPA受体从细胞表面移除的机制尚未完全了解。在本研究中，我们表明，在培养的海马神经元中，小干扰RNA（siRNA）介导的含无菌α和Toll/白细胞介素受体基序1（SARM1）的敲低可防止N-甲基-D-天冬氨酸（NMDA）诱导的细胞表面AMPA受体减少。然而，对照RNA不影响NMDA介导的AMPA受体转运。在SARM1敲低的神经元中过表达抗siRNA形式的SARM1可恢复AMPA受体转运。然而，在SARM1敲低的神经元中过表达缺乏线粒体运输信号的SARM1并不能恢复NMDA依赖性AMPA受体内吞作用。此外，抑制SARM1的NADase活性可阻断NMDA诱导的细胞表面AMPA受体减少。这些结果表明，SARM1的线粒体定位和NADase活性对于海马神经元中NMDA受体依赖性AMPA受体内化都是必不可少的。
