Sigma-1 Receptor Knockout Impairs Neurogenesis in Dentate Gyrus of Adult Hippocampus Via Down-Regulation of NMDA Receptors

Aims This study investigated the influence of sigma-1 receptor (sigma R-1) deficiency on adult neurogenesis. Methods We employed 8-week-old male sigma R-1 knockout (sigma R-1(-/-)) mice to examine the proliferation and differentiation of progenitor cells, and the survival and neurite growth of newborn neurons in hippocampal dentate gyrus (DG). Results In comparison with wild-type (WT) littermates, the numbers of 24-h-old BrdU(+) cells and Ki67(+) cells in sigma R-1(-/-) mice increased, while the number of 28-day-old BrdU(+) cells decreased without changes in proportion of BrdU(+)/NeuN(+) cells and BrdU(+)/GFAP(+) cells. The neurite density of newborn neurons was slightly reduced in sigma R-1(-/-) mice. In DG granular cells, N-methyl-d-aspartate (NMDA)-activated current (I-NMDA) and phosphorylation of NMDA receptor (NMDAr) NR2B were reduced in sigma R-1(-/-) mice without the alteration of NR2B expression and membrane properties compared to WT mice. The NR2B antagonist abolished the difference in I-NMDA between sigma R-1(-/-) mice and WT mice. The application of NMDAr agonist in sigma R-1(-/-) mice prevented the over-proliferation of cells and reduction in newborn neurons, but it had no effects on the hypoplastic neurite. The administration of NMDAr antagonist in WT mice enhanced the cell proliferation and depressed the survival of newborn neurons. Conclusion The sigma R-1 deficiency impairs neurogenesis in DG through down-regulation of NMDArs.