Chronic D-serine reverses arc expression and partially rescues dendritic abnormalities in a mouse model of NMDA receptor hypofunction

Neurochem Int. 2014 Sep;75:76-8. doi: 10.1016/j.neuint.2014.05.015. Epub 2014 Jun 7.


Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that is expressed almost exclusively in glutamatergic neurons. Arc protein is enriched in the postsynaptic density (PSD) and colocalizes with the N-methyl-D-aspartate receptor (NMDAR) complex. Arc transcription is positively modulated by NMDAR activity and is important for dendritic spine plasticity. Genetic ablation of serine racemase (SR-/-), the enzyme that converts L-serine to D-serine, a coagonist at the NMDAR, reduces dendritic spine density in the hippocampus. Here we demonstrate that SR deficient (SR-/-) mice also have reduced Arc protein expression in the hippocampus that can be reversed with chronic D-serine administration in adulthood. Furthermore, D-serine treatment partially rescues the hippocampal spine deficit in SR-/- mice. These results demonstrate the importance of D-serine in regulating the hippocampal expression of Arc in vivo. In addition, our findings underscore the potential utility of using the glycine modulatory site agonist D-serine to treat disorders that exhibit Arc and dendritic spine dysregulation as a consequence of NMDAR hypofunction, such as schizophrenia.

Keywords: Activity-regulated cytoskeleton-associated protein; Dendritic spines; Dentate gyrus; Schizophrenia; Serine racemase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Male
  • Mice
  • Mice, Knockout
  • Racemases and Epimerases / genetics
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Serine / chemistry
  • Serine / pharmacology*
  • Stereoisomerism


  • Receptors, N-Methyl-D-Aspartate
  • Serine
  • Racemases and Epimerases
  • serine racemase