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

Abstract

New neurons are continuously generated from resident pools of neural stem and precursor cells (NSPCs) in the adult brain. There are multiple pathways through which adult neurogenesis is regulated, and here we review the role of the N-methyl-D-aspartate receptor (NMDAR) in regulating the proliferation of NSPCs in the adult hippocampus. Hippocampal-dependent learning tasks, enriched environments, running, and activity-dependent synaptic plasticity, all potently up-regulate hippocampal NSPC proliferation. We first consider the requirement of the NMDAR in activity-dependent synaptic plasticity, and the role the induction of synaptic plasticity has in regulating NSPCs and newborn neurons. We address how specific NMDAR agonists and antagonists modulate proliferation, both in vivo and in vitro, and then review the evidence supporting the hypothesis that NMDARs are present on NSPCs. We believe it is important to understand the mechanisms underlying the activation of adult neurogenesis, given the potential that endogenous stem cell populations have for repopulating the hippocampus with functional new neurons. In conditions such as age-related memory decline, neurodegeneration and psychiatric disease, mature neurons are lost or become defective; as such, stimulating adult neurogenesis may provide a therapeutic strategy to overcome these conditions. The adult brain continuously generates new neurons throughout life. These adult-born neurons arise from endogenous neural stem and precursor cells (NSPCs), which primarily reside within two neurogenic niches: the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus, and the subventricular zone (SVZ) of the lateral ventricles. In the 20 years since adult mammalian neurogenesis started receiving substantial attention [1,2], scientists have made great progress in understanding the mechanisms that regulate stem cell maintenance, proliferation, differentiation, maturation and integration [3,4]. Early on, extrinsic cues from the environment, such as learning [5], physical activity [6], and enriched environments [7,8], were found to potently enhance hippocampal neurogenesis. It was not long before a link was made to synaptic plasticity [9], which is also enhanced by physical exercise [10], and is widely accepted as the synaptic mechanism underlying hippocampal learning and memory [11]. Synaptic plasticity and adult hippocampal neurogenesis are intimately linked, as long-term potentiation (LTP), an activity-dependent change in synaptic efficacy, can influence the activation and proliferation of NSPCs in the DG (e.g., [12]), as well as the survival of newborn neurons (e.g., [13]). These newborn neurons have biophysical characteris-

The Long Run: Neuroprotective Effects of Physical Exercise on Adult Neurogenesis from Youth to Old Age

“…Research on rodent has begun to elucidate the molecular and cellular mechanisms activated by voluntary running that are likely to sustain the positive effect of physical exercise on cognition and memory, which is mediated, at least in part, by increased angiogenesis, synaptogenesis and hippocampal neurogenesis. In the hippocampus, structural modifications of dendritic morphology are thought to play a major role in neuronal functioning [ 223 ]; in this context, adult neurogenesis in the DG provides additional plasticity to the hippocampal circuitry [ 224 , 225 ]. The increase of neural stem/progenitor cells in the DG neurogenic niche, together with the increase of synaptic plasticity in existing neurons, may be essential mediators of the improvement of hippocampus-dependent memory exerted by physical exercise.…”

Excessive activation of NMDA receptor inhibits the protective effect of endogenous bone marrow mesenchymal stem cells on promoting alveolarization in bronchopulmonary dysplasia

“…Both systemic administration of the competitive NMDAR antagonist CGP43487 and MK-801 treatments induced a twofold increase in the number of [ 3 H]thymidine-labeled cells in the granule cell layer compared with the control group (6). In contrast, treatment with NMDA, the major agonist of the NMDAR, resulted in a significant reduction in proliferation in the granule cell layer (6,41). In this study, we found that the proliferation ability and cell viability of bone marrow MSCs of the intrauterine hypoxia group were significantly reduced compared with those of the control group in vitro.…”

“…The results of our previous study also revealed NMDA receptor expression in MSCs extracted from mouse bone marrow (21). Studies also revealed that direct modulation of NMDARs alters hippocampal neural stem and precursor cell proliferation in the adult hippocampus (41). Both systemic administration of the competitive NMDAR antagonist CGP43487 and MK-801 treatments induced a twofold increase in the number of [ 3 H]thymidine-labeled cells in the granule cell layer compared with the control group (6).…”

Introduction to the thematic issue “From brain function to therapy”

“…In our review, we discuss the role of the N-methyl-D-aspartate receptor (NMDAR) in regulating the pools of neural stem and precursor cells in the hippocampus, which play such a crucial part in regulating the neurogenesis that underpins hippocampal learning and memory. Enhancement of this neurogenic process may be potentially used to ameliorate the effects of dementia [6]. In collaboration with Professor Jürgen Götz's laboratory (QBI), the He laboratory further explores processes underlying the major form of dementia, Alzheimer's disease (AD).…”