Inoue Ran, Talukdar Gourango, Takao Keizo, Miyakawa Tsuyoshi, Mori Hisashi
Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Life Science Research Center, University of Toyama, Toyama, Japan.
Front Mol Neurosci. 2018 May 22;11:161. doi: 10.3389/fnmol.2018.00161. eCollection 2018.
Extinction-based exposure therapy is widely used for the treatment of anxiety disorders, such as post-traumatic stress disorder (PTSD). D-serine, an endogenous co-agonist at the glycine-binding site of the -methyl-D-aspartate-type glutamate receptor (NMDAR), has been shown to be involved in extinction of fear memory. Recent findings suggest that the length of time between the initial learning and an extinction session is a determinant of neural mechanism involved in fear extinction. However, how D-serine is involved in extinction of fear memory at different timings remains unclear. In the present study, we investigated the role of D-serine in immediate, delayed and post-retrieval extinction (P-RE) of contextual fear memory using wild-type (WT) and serine racemase (SRR) knockout (KO) mice that exhibit 90% reduction in D-serine content in the hippocampus. We found that SRR disruption impairs P-RE, facilitates immediate extinction (IE), but has no effect on delayed extinction (DE) of contextual fear memories. The impaired P-RE of contextual fear memory in SRRKO mice was associated with increased expression of the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPAR) in the hippocampal synaptic membrane fraction after P-RE, and this increase of AMPAR and impaired P-RE were rescued by the administration of D-serine to SRRKO mice. Our findings suggest that D-serine is differentially involved in the regulation of contextual fear extinction depending on the timing of behavioral intervention, and that combining D-serine or other drugs, enhancing the NMDAR function, with P-RE may achieve optimal outcomes for the treatment of PTSD.
基于消退的暴露疗法被广泛用于治疗焦虑症，如创伤后应激障碍（PTSD）。D-丝氨酸是α-甲基-D-天冬氨酸型谷氨酸受体（NMDAR）甘氨酸结合位点的内源性共激动剂，已被证明参与恐惧记忆的消退。最近的研究结果表明，初始学习与消退训练之间的时间长度是恐惧消退所涉及神经机制的一个决定因素。然而，D-丝氨酸在不同时间点如何参与恐惧记忆的消退仍不清楚。在本研究中，我们使用野生型（WT）和丝氨酸消旋酶（SRR）基因敲除（KO）小鼠，研究了D-丝氨酸在情境恐惧记忆的即时、延迟和检索后消退（P-RE）中的作用，这些小鼠海马中的D-丝氨酸含量降低了90%。我们发现，SRR基因敲除会损害P-RE，促进即时消退（IE），但对情境恐惧记忆的延迟消退（DE）没有影响。SRR基因敲除小鼠情境恐惧记忆的P-RE受损与P-RE后海马突触膜部分α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体（AMPAR）的GluA1亚基表达增加有关，向SRR基因敲除小鼠施用D-丝氨酸可挽救AMPAR的这种增加和受损的P-RE。我们的研究结果表明，D-丝氨酸根据行为干预的时间不同，以不同方式参与情境恐惧消退的调节，并且将D-丝氨酸或其他增强NMDAR功能的药物与P-RE相结合可能会为PTSD的治疗带来最佳效果。
