d-serine enhances extinction of auditory cued fear conditioning via ERK1/2 phosphorylation in mice |
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Authors: | Shingo Matsuda Daisuke Matsuzawa Ken Nakazawa Chihiro Sutoh Hiroyuki Ohtsuka Daisuke Ishii Haruna Tomizawa Masaomi Iyo Eiji Shimizu |
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Institution: | 1. Department of Integrative Neurophysiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan;2. Department of Psychiatry, Chiba University Graduate School of Medicine, Japan |
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Abstract: | Several lines of evidence suggest that the N-methyl-D-aspartate (NMDA) receptor plays a significant role in fear conditioning and extinction. However, our knowledge of the role of d-serine, an endogenous ligand for the glycine site of the NMDA receptor, in fear extinction is quite limited compared to that of d-cycloserine, an exogenous partial agonist for the same site. In the current study, we examined the effects of d-serine on fear extinction and phosphorylation of extracellular signal-regulated kinase (ERK) in the hippocampus, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC) during the process of fear extinction. Systemic administrations of d-serine (2.7 g/kg, i.p.) with or without the ERK inhibitor SL327 (30 mg/kg, i.p.) to C57BL/6 J mice were performed before fear extinction in a cued fear conditioning and extinction paradigm. Cytosolic and nuclear ERK 1/2 phosphorylation in the hippocampus, BLA, and mPFC were measured 1 h after extinction (E1h), 24 h after extinction (E24h), and 1 h after recall (R1h) by Western blotting. We found that d-serine enhanced the extinction of fear memory, and the effects of d-serine were reduced by the ERK phosphorylation inhibitor SL327. The Western blot analyses showed that d-serine significantly increased cytosolic ERK 2 phosphorylation at E1h in the hippocampus and cytosolic ERK 1/2 phosphorylation at R1h in the BLA. The present study suggested that d-serine might enhance fear extinction through NMDA receptor-induced ERK signaling in mice, and that d-serine has potential clinical importance for the treatment of anxiety disorders. |
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Keywords: | BLA basolateral amygdala CS conditioned stimulus DAO D-amino acid oxidase DCS D-cycloserine DMSO dimethyl sulfoixde ERK extracellular signal-regulated kinase i p intraperitoneal MEK mitogen-activated protein kinase kinases mPFC medial prefrontal cortex NMDA receptor N-methyl-D-aspartate receptor pERK phosphorylated ERK PTSD posttraumatic stress disorder tERK total ERK US unconditioned stimulus |
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