title: Chronic D-serine reverses arc expression and partially rescues dendritic abnormalities in a mouse model of NMDA receptor hypofunction.
abstract: 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.
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Darrick T
authors.initials: DT
authors.lastname: Balu
authors.affiliation: Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, Belmont, MA 02478, USA. Electronic address: joseph_coyle@hms.harvard.edu.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Coyle
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019998:Racemases and Epimerases / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012694:Serine / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D000099300:Serine Racemase
chemical_list: D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase
keywords: Activity-regulated cytoskeleton-associated protein; Dendritic spines; Dentate gyrus; Schizophrenia; Serine racemase