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.

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

Fig. 1

Chronic D-serine administration restores Arc protein levels in the hippocampus of SR−/− mice. Protein levels of Arc were measured in the hippocampus of WT (n=12; black bars), SR−/− (n=6; white bars), and SR−/− mice treated with D-serine (n=6; gray bars). Asterisk (*) indicates significant difference from the WT vehicle group and # indicates significant difference from the SR−/− group (p < 0.01). All values represent the means ± SEM.

Fig. 2

Chronic D-serine administration partially rescues the dendritic spine deficit in the dentate gyrus of SR−/− mice. Spine density on dentate granule neurons (5–6 neurons/animal) was compared between WT (n=7; black bars), SR−/− (n = 5; white bars), and SR−/− mice administered D-serine (n=6; gray bars). Spine density is expressed as the number of spines per 10μm of dendrite. Asterisk (*) indicates significant difference from the WT vehicle group (p < 0.01). All values represent the means ± SEM.