title: d-serine enhances extinction of auditory cued fear conditioning via ERK1/2 phosphorylation in mice.
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/6J 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 1h after extinction (E1h), 24h after extinction (E24h), and 1h 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.
authors.affiliation: Department of Integrative Neurophysiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsuda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsuzawa
authors.forename: Ken
authors.initials: K
authors.lastname: Nakazawa
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sutoh
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohtsuka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishii
authors.forename: Haruna
authors.initials: H
authors.lastname: Tomizawa
authors.forename: Masaomi
authors.initials: M
authors.lastname: Iyo
authors.forename: Eiji
authors.initials: E
authors.lastname: Shimizu
mesh_terms: D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003214:Conditioning, Classical / Q000187:drug effects*; D003463:Cues; D005108:Extinction, Psychological / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005239:Fear; D008297:Male; D051379:Mice; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012694:Serine / Q000494:pharmacology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D048049:Extracellular Signal-Regulated MAP Kinases