School of Food and Biotechnology, Guangdong Industry Polytechnic, Guangzhou 510300, China.
Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
Neuroscience. 2022 Aug 21;498:235-248. doi: 10.1016/j.neuroscience.2022.07.009. Epub 2022 Jul 18.
Endocytosis of GluA2-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in CA1 of the hippocampus regulates forgetting; deficits in forgetting nociceptive memory can induce serious stress disorders. As a transporter of GluA2-containing AMPAR, the functions of glutamate receptor interacting protein 1 (GRIP1) in forgetting and possible stress responses remain unclear. Lentivirus-mediated interference of GRIP1 expression or function in the dorsal CA1 of the hippocampus in mice indicated that GRIP1 overexpression enhanced spatial memory, impaired forgetting in a Barnes maze, and induced anxiety-like behavior in the open field and elevated plus-maze test. In contrast, GRIP1 knockdown impaired learning capacity. Furthermore, inhibition of the PDZ2 and PDZ4/5 domains of GRIP1 and GluA2-dn enhanced learning capacity, whereas GluA2-dn impaired spatial memory; inhibition of the PDZ2 and PDZ4/5 domains of GRIP1 also decreased forgetting capacity to some extent. Importantly, inhibition of both the PDZ2 and PDZ4/5 domains of GRIP1 induced anxiety-like behavior but not GluA2-dn. Furthermore, optogenetic control of both GluA1 and GluA2 insertion into the postsynaptic membrane impaired memory and induced anxiety-like behavior. In vitro experiments showed that GRIP1-ov and -dn, inhibition of PDZ2 and PDZ4/5 domains of GRIP1, and GluA2-dn decreased glycine-induced GluA1 and GluA2 exocytosis; meanwhile, GRIP1-ov and -dn, and interference of PDZ2 and PDZ4/5 domains of GRIP1 blocked AMPA- and NMDA-induced GluA1 and GluA2 endocytosis. Overall, these results suggest that GRIP1 drives AMPA receptor endocytosis and exocytosis bidirectionally; furthermore, GRIP1-induced stabilization of anchoring postsynaptic GluA1 and GluA2 impairs forgetting and induces anxiety-like behavior. GRIP1 may provide a potential therapeutic target in posttraumatic syndromes and anxiety disorders.
内吞 GluA2 包含的 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPAR) 在海马 CA1 中调节遗忘；疼痛记忆遗忘缺陷可导致严重的应激障碍。谷氨酸受体相互作用蛋白 1 (GRIP1) 作为 GluA2 包含的 AMPAR 的转运体，其在遗忘和可能的应激反应中的功能尚不清楚。在小鼠海马 CA1 背侧用慢病毒介导的 GRIP1 表达或功能干扰表明，GRIP1 过表达增强了空间记忆，损害了巴恩斯迷宫中的遗忘，诱导了旷场和高架十字迷宫测试中的焦虑样行为。相反，GRIP1 敲低损害了学习能力。此外，抑制 GRIP1 的 PDZ2 和 PDZ4/5 结构域以及 GluA2-dn 增强了学习能力，而 GluA2-dn 损害了空间记忆；抑制 GRIP1 的 PDZ2 和 PDZ4/5 结构域也在一定程度上降低了遗忘能力。重要的是，抑制 GRIP1 的 PDZ2 和 PDZ4/5 结构域均诱导了焦虑样行为，但 GluA2-dn 没有。此外，光遗传学控制 GluA1 和 GluA2 插入突触后膜均损害了记忆并诱导了焦虑样行为。体外实验表明，GRIP1-ov 和 -dn、抑制 GRIP1 的 PDZ2 和 PDZ4/5 结构域以及 GluA2-dn 降低了甘氨酸诱导的 GluA1 和 GluA2 胞吐；同时，GRIP1-ov 和 -dn 以及抑制 GRIP1 的 PDZ2 和 PDZ4/5 结构域阻断了 AMPA 和 NMDA 诱导的 GluA1 和 GluA2 内吞。总之，这些结果表明，GRIP1 双向驱动 AMPA 受体的内吞和胞吐；此外，GRIP1 诱导的锚定突触后 GluA1 和 GluA2 的稳定损害了遗忘并诱导了焦虑样行为。GRIP1 可能为创伤后综合征和焦虑障碍提供潜在的治疗靶点。
