Activation of NMDA receptors increases proliferation and differentiation of hippocampal neural progenitor cells

Abstract

The prolonged effects of N-methyl-D-aspartate (NMDA) receptor activation on the proliferation and differentiation of hippocampal neural progenitor cells (NPCs) were studied. Under conditions of mitogen-mediated proliferation, a single NMDA pulse (5 μM) increased the fraction of 5-bromo-2-deoxyuridine (BrdU)-positive (BrdU+) cells after a delay of 72 hours. Similarly, a single systemic injection of NMDA (100 mg/kg) increased the number of BrdU+ cells in the dentate gyrus (DG) after 28 days, but not after 3 days. NMDA receptor activation induced an immediate influx of Ca2+ into the NPCs and the NPCs expressed and released vascular endothelial growth factor (VEGF) in an NMDA receptor-dependent manner within 72 hours. With repetitive stimulation at the same dose, NMDA stimulated the acquisition of a neuronal phenotype accompanied by an increase in the expression of proneural basic helix-loop-helix (bHLH) factors. Together these findings suggest that neurogenesis in the developing brain is likely to be both directly and indirectly regulated by complex interactions between Ca2+ influx and excitation-releasable cytokines, even at mild levels of excitation. In addition, our results are the first to show that stimulation of NPCs may lead to either proliferation or neuronal differentiation, depending on the level of NMDA receptor activation.

Prenatal NMDA Receptor Antagonism Impaired Proliferation of Neuronal Progenitor, Leading to Fewer Glutamatergic Neurons in the Prefrontal Cortex

“…Neurospheres derived from the embryonic rat brain express the NR1 and NR2B subunits of the NMDA receptor and show reductions in diameter and number (Mochizuki et al, 2007). Furthermore, the activation of NMDA receptors increases the proliferation of neuronal progenitors in the developing hippocampus (Joo et al, 2007) and striatum (Luk et al, 2003) as well. These findings are consistent with the present results.…”

Multiple signaling pathways involved in stimulation of osteoblast differentiation by N-methyl-D-aspartate receptors activation in vitro

“…NMDA has been shown to promote the proliferation and differentiation of hippocampal neural progenitor cells (NPCs) in vitro by activating NMDA receptors [9] . NMDA is mitogenic for MC3T3-E1 osteoblastic cells and glutamate has been reported to promote the viability of primary human osteoblasts in vitro [10] .…”

The role of the N-methyl-d-aspartate receptor in the proliferation of adult hippocampal neural stem and precursor cells

“…For instance, Joo and colleagues [66] have shown that proliferation is positively regulated by NMDAR activity in the embryonic hippocampus, and similar results have been shown in the P0 hippocampus [72]. On the other hand, treatment of P0 cultures with Ro 25-6981 or MK801 can significantly decrease neurosphere formation [72].…”

“…Instead, continuous activation of the NMDAR is more likely to shut down actively proliferating stem cells to protect them from NMDAR-mediated excitotoxicity. Indeed, some in vitro studies have used sustained concentrations of NMDA that were shown to cause excitotoxic death of the NSPCs (e.g., [66]), so it is not surprising that proliferation of NSPCs can be inhibited under these conditions. Nevertheless, other studies report that cell death is not induced by the NMDA treatment (e.g., [62]).…”

“…Joo and colleagues [66] have shown that while NSPC proliferation is increased in the SGZ 3 days after MK801 treatment, and is decreased after NMDA treatment, the opposite results were observed 28 d after treatment-MK801 reduced the number of BrdU-labelled cells while NMDA increased BrdU numbers, indicating that activation of the NMDAR had increased the survival of proliferating cells [66].…”