NMDA and benzodiazepine receptors have synergistic and antagonistic effects on precursor cells in adult hippocampal neurogenesis

Petrus, Dominique Sebastian; Fabel, Klaus; Kronenberg, Golo; Winter, Christine; Steiner, Barbara; Kempermann, Gerd

doi:10.1111/j.1460-9568.2008.06579.x

Cited by 42 publications

(37 citation statements)

References 37 publications

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“…Interestingly, these treatments did not disrupt basal neurogenesis, a finding consistent with some (35), but not all, previous studies (36,37). The discrepancy between these studies might be related to differences in drug regimens, species, strains, and sex, all of which are known to influence neurogenesis (2,38).…”

Section: Discussionsupporting

confidence: 82%

“…NMDA antagonists might act directly on newborn neurons. Although the presence of NMDARs on dividing cells is controversial (19,37), these receptors have been shown to respond to changes in glutamate levels (39). In vitro application of NMDA on hippocampal precursor cells increased neuronal differentiation, whereas treatment with the antagonist APV decreased neuronal differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons

Tronel

Fabre

Charrier

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

186

187

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Neurogenesis in the hippocampus is characterized by the birth of thousand of cells that generate neurons throughout life. The fate of these adult newborn neurons depends on life experiences. In particular, spatial learning promotes the survival and death of new neurons. Whether learning influences the development of the dendritic tree of the surviving neurons (a key parameter for synaptic integration and signal processing) is unknown. Here we show that learning accelerates the maturation of their dendritic trees and their integration into the hippocampal network. We demonstrate that these learning effects on dendritic arbors are homeostatically regulated, persist for several months, and are specific to neurons born during adulthood. Finally, we show that this dendritic shaping depends on the cognitive demand and relies on the activation of NMDA receptors. In the search for the structural changes underlying long-term memory, these findings lead to the conclusion that shaping neo-networks is important in forming spatial memories.adult neurogenesis | memory | spatial learning | hippocampus | dendrite I n the search for the mechanisms underlying long-term memory formation, structural changes have been proposed to play a major role (1). Adult neurogenesis, a novel form of structural plasticity, occurs in the dentate gyrus (DG), a key structure in processing spatial relational memory (2). Adult neurogenesis in the DG is a complex, multistep process that starts with the proliferation of neural precursors residing in the dentate subgranular layer (2). At least 50% of the daughter cells die within a few days after their birth. The adult-born cells that survive this initial period of cell death differentiate mainly into granule neurons. These new mature neurons are synaptically integrated into the dentate network, where they receive functional inputs (3) and form functional synapses with their target cells (4).Adult-born neurons contribute to the formation of memories, particularly spatial memory as measured in the water maze (5, 6). Reciprocally, spatial learning has been shown to influence adult neurogenesis (7). We have shown that during spatial learning and similar to the selective stabilization process observed during brain development, neuronal networks are sculpted by a tightly regulated selection and suppression of different populations of newly born neurons (8). This homeostatic regulation of the numbers of newly born neurons is important for spatial memory, because its alteration leads to memory deficits (8, 9).One of the requirements for the new neurons to process information is the development of extensive dendritic arbors capable of receiving and integrating complex spatiotemporal patterns of synaptic inputs (4). Whether learning influences such a dendritic development is unknown. To address this issue, we used doublecortin (Dcx) and retroviral labeling to examine to what extent spatial learning in the water maze affects the dendritic morphology of adult-born neurons. Furthermore, we investigated whether the ...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons

Tronel

Fabre

Charrier

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

186

187

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“…At 4 weeks, the number of BrdU-labelled cells that retained GFP was reduced, while the number of BrdU-positive cells co-labelled with NeuN had increased. These results suggest that NMDAR antagonism promotes the proliferation of stem cells, stimulates their progression through the neurogenic pathway, and increases neuronal differentiation at the expense of the NSPC population [67].…”

Section: Direct Modulation Of Nmdars Alters Nspc Proliferation In Thementioning

confidence: 80%

“…By 2 weeks of age, clear GluN1 and GluN2B staining was observed in most BrdU-labelled newborn neurons, and cells co-stained with DCX showed a similar pattern of GluN1 and GluN2B expression [73]. In another study, Petrus and colleagues did not find any GluN1 immunoreactivity in nestin-GFP positive NSPCs in the SGZ of adult mice [67]. As these in vivo studies report mixed results as to whether NSPCs express NMDARs, further investigation is warranted, given the strong evidence that NMDARs modulate NSPC proliferation.…”

Section: Nmdar Subunit Expression On Nspcsmentioning

confidence: 95%

“…To ascertain the identity of the cells within the neurogenic pathway that proliferate in response to NMDAR blockade, Petrus and colleagues [67] utilised adult mice expressing GFP under the nestin promoter, as well as immunohistochemical markers of stem cell identity. One hour following MK801 treatment, more NSPCs had entered the cell cycle, identified by nestin-GFP expression and BrdU incorporation, while the number of proliferating progenitor cells expressing nestin and DCX did not change compared to saline controls.…”

Section: Direct Modulation Of Nmdars Alters Nspc Proliferation In Thementioning

confidence: 99%

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

Taylor

Bartlett

2014

Sci. China Life Sci.

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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-

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Cell age–specific vulnerability of neurons to anesthetic toxicity

Hofacer

Deng

Ward

et al. 2013

Annals of Neurology

115

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Objective Anesthetics have been linked to widespread neuronal cell death in neonatal animals. Epidemiological human studies have associated early childhood anesthesia with long-term neurobehavioral abnormalities, raising substantial concerns that anesthetics may cause similar cell death in young children. However, key aspects of the phenomenon remain unclear, such as why certain neurons die, whereas immediately adjacent neurons are seemingly unaffected, and why the immature brain is exquisitely vulnerable, whereas the mature brain seems resistant. Elucidating these questions is critical for assessing the phenomenon’s applicability to humans, defining the susceptible age, predicting vulnerable neuronal populations, and devising mitigating strategies. Methods This study examines the effects of anesthetic exposure on late- and adult-generated neurons in newborn, juvenile, and adult mice, and characterizes vulnerable cells using birth-dating and immunohistochemical techniques. Results We identify a critical period of cellular developmental during which neurons are susceptible to anesthesia-induced apoptosis. Importantly, we demonstrate that anesthetic neurotoxicity can extend into adulthood in brain regions with ongoing neurogenesis, such as dentate gyrus and olfactory bulb. Interpretation Our findings suggest that anesthetic vulnerability reflects the age of the neuron, not the age of the organism, and therefore may potentially not only be relevant to children but also to adults undergoing anesthesia. This observation further predicts differential heightened regional vulnerability to anesthetic neuroapoptosis to closely follow the distinct regional peaks in neurogenesis. This knowledge may help guide neurocognitive testing of specific neurological domains in humans following exposure to anesthesia, dependent on the individual’s age during exposure.

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NMDA and benzodiazepine receptors have synergistic and antagonistic effects on precursor cells in adult hippocampal neurogenesis

Cited by 42 publications

References 37 publications

Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons

Spatial learning sculpts the dendritic arbor of adult-born hippocampal neurons

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

Cell age–specific vulnerability of neurons to anesthetic toxicity

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