D-serine enhances extinction of auditory cued fear conditioning via ERK1/2 phosphorylation in mice

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 (ERR) 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 ERR 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 ERR 1/2 phosphorylation in the hippocampus, BLA, and mPFC were measured 1 h after extinction (El h), 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 ERR phosphorylation inhibitor SL327. The Western blot analyses showed that D-serine significantly increased cytosolic ERR 2 phosphorylation at El h in the hippocampus and cytosolic ERR 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. (C) 2010 Elsevier Inc. All rights reserved.