Effects of Chronic D-Serine Elevation on Animal Models of Depression and Anxiety-Related Behavior

PLoS One. 2013 Jun 21;8(6):e67131. doi: 10.1371/journal.pone.0067131. Print 2013.


NMDA receptors are activated after binding of the agonist glutamate to the NR2 subunit along with a co-agonist, either L-glycine or D-serine, to the NR1 subunit. There is substantial evidence to suggest that D-serine is the most relevant co-agonist in forebrain regions and that alterations in D-serine levels contribute to psychiatric disorders. D-serine is produced through isomerization of L-serine by serine racemase (Srr), either in neurons or in astrocytes. It is released by astrocytes by an activity-dependent mechanism involving secretory vesicles. In the present study we generated transgenic mice (SrrTg) expressing serine racemase under a human GFAP promoter. These mice were biochemically and behaviorally analyzed using paradigms of anxiety, depression and cognition. Furthermore, we investigated the behavioral effects of long-term administration of D-serine added to the drinking water. Elevated brain D-serine levels in SrrTg mice resulted in specific behavioral phenotypes in the forced swim, novelty suppression of feeding and olfactory bulbectomy paradigms that are indicative of a reduced proneness towards depression-related behavior. Chronic dietary D-serine supplement mimics the depression-related behavioral phenotype observed in SrrTg mice. Our results suggest that D-serine supplementation may improve mood disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety Disorders / drug therapy*
  • Anxiety Disorders / genetics
  • Anxiety Disorders / metabolism*
  • Anxiety Disorders / pathology
  • Behavior, Animal / drug effects*
  • Depression / drug therapy*
  • Depression / genetics
  • Depression / metabolism*
  • Depression / pathology
  • Disease Models, Animal
  • Glial Fibrillary Acidic Protein / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Promoter Regions, Genetic
  • Racemases and Epimerases / genetics
  • Racemases and Epimerases / metabolism
  • Serine* / pharmacokinetics
  • Serine* / pharmacology


  • Glial Fibrillary Acidic Protein
  • Serine
  • Racemases and Epimerases
  • serine racemase

Grant support

This work was supported by grants from the Federal Ministry of Education and Research (NGFN2 01G10474, NGFN-MOODS FKZ 01GS08144 and 01GW0511). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.