Cameron, H. A., McEwen, B. S. & Gould, E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J. Neurosci. 15, 4687−4692

Laboratory of Neuroendocrinology, Rockefeller University, New York, New York 10021, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/1995; 15(6):4687-92.
Source: PubMed


The effects of afferent input and N-methyl-D-aspartate (NMDA) receptor activation on neurogenesis were examined in an intact system, the rat dentate gyrus, where neurons are naturally born in the adult. In the adult dentate gyrus, activation of NMDA receptors rapidly decreased the number of cells synthesizing DNA, whereas blockade of NMDA receptors rapidly increased the number of cells in the S phase identified with 3H-thymidine. Acute treatment with NMDA receptor antagonists increased the birth of neurons and increased the overall density of neurons in the granule cell layer. Lesion of the entorhinal cortex, the main excitatory afferent population to the granule neurons, also increased the birth of cells in the dentate gyrus. These results suggest that adult neurogenesis in the dentate gyrus of the rat is altered by afferent input, via NMDA receptors, and may be regulated naturally by endogenous excitatory amino acids.

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Available from: Heather Cameron, Jan 10, 2015
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    • "This extreme form of structural remodeling, similar to many other forms of experience-dependent plasticity, requires activation of NMDA receptors (NMDARs) (Platel and Kelsch, 2013). Blockade of NMDARs rapidly increases the proliferation of neural precursor cells, whereas stimulation of NMDARs promotes neuronal fate specification (Cameron et al., 1995; Deisseroth et al., 2004). Moreover, deletion of the NMDAR subunit NR1 reduces the survival rate of adult-born GCs (Tashiro et al., 2006a). "
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    ABSTRACT: NMDA receptor (NMDAR)-dependent forms of synaptic plasticity are thought to underlie the assembly of developing neuronal circuits and to play a crucial role in learning and memory. It remains unclear how NMDAR might contribute to the wiring of adult-born granule cells (GCs). Here we demonstrate that nascent GCs lacking NMDARs but rescued from apoptosis by overexpressing the pro-survival protein Bcl2 were deficient in spine formation. Insufficient spinogenesis might be a general cause of cell death restricted within the NMDAR-dependent critical time window for GC survival. NMDAR loss also led to enhanced mushroom spine formation and synaptic AMPAR activity throughout the development of newborn GCs. Moreover, similar elevated synapse maturation in the absence of NMDARs was observed in neonate-generated GCs and CA1 pyramidal neurons. Together, these data suggest that NMDAR operates as a molecular monitor for controlling the activity-dependent establishment and maturation rate of synaptic connections between newborn neurons and others.
    Full-text · Article · Oct 2015 · eLife Sciences
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    • "The niche concept of stem cell biology proposes that stem cells require local environmental cues to control self-renewal and differentiation (Guilak et al., 2009; Scadden, 2006). In the hippocampus, this mediation will take place at several levels (Kempermann, 2011), presumably in parallel and in an interactive manner, involving direct cell-to-cell signaling via gap-junctions (Kunze et al., 2009), paracrine signals such as Wnt (Lie et al., 2005), neurotransmitters, most notably glutamate (Cameron et al., 1995) and GABA (Ge et al., 2006; Wang et al., 2005), as well as systemic factors, including growth factors and hormones. A number of studies have addressed the same issue for the SVZ. "
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    ABSTRACT: The niche concept of stem cell biology proposes a functional unit between the precursor cells and their local microenvironment, to which several cell types might contribute by cell-cell contacts, extracellular matrix, and humoral factors. We here established three co-culture models (with cell types separated by membrane) for both adherent monolayers and neurospheres to address the potential influence of different niche cell types in the neurogenic zone of the adult hippocampus of mice. Astrocytes and endothelial cells enhanced precursor cell proliferation and neurosphere formation. Endothelial factors also led to a prolonged increase in proliferation after growth factor withdrawal, which otherwise induces differentiation. All niche cell types enhanced cell survival in monolayer cultures, endothelial cells also stimulated neuronal differentiation. A parallel trend elicited by astrocytes did not reach conventional statistical significance. Pericytes had variable effects here. We did not observe changes in differentiation in neurosphere co-cultures. In summary, our data indicate that in precursor cell culture protocols survival could be improved by adding as yet unknown factors physiologically contributed by astrocytes and endothelial cells. Our findings also underscore the complexity of the niche and the differential impact of factors from the different sources on distinct aspects of neuronal development. With the help of the models presented here, identification of these factors and their specific biological activity can now be initiated.
    Full-text · Article · Oct 2015 · Stem Cell Research
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    • "Activation of NMDA receptors was shown to rapidly decrease DG cell proliferation, while blockade of the NMDA receptors brought an increase of neurogenesis. When the excitatory input to the DG was severed, an increase in cell proliferation was also observed (Cameron et al. 1995). In a transgenic animal study, it was shown that decreased expression of NR1 subunit of NMDA receptor, which is essential for the ion channel functioning of NMDA, led to an increase in DG neurogenesis (Bursztajn et al. 2007). "
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    ABSTRACT: Abuse of cough mixture is increasingly prevalent worldwide. Clinical studies showed that chronic consumption of cough mixture at high dosages may lead to psychiatric symptoms, especially affective disturbances, with the underlying mechanisms remain elusive. The present study aims at exploring the effect of repeated, high-dose dextromethorphan (DXM, a common active component of cough mixture) treatment on adult hippocampal neurogenesis, which is associated with pathophysiology of mood disturbances. After treatment with a high-dose of DXM (40 mg/kg/day) for 2 weeks, Sprague-Dawley rats showed increased depression-like behavior when compared to the control animals. Neurogenesis in the hippocampus was suppressed by DXM treatment, which was indicated by decreases in number of proliferative cells and doublecortin (an immature neuron marker)-positive new neurons. Furthermore, the dendritic complexity of the immature neurons was suppressed by DXM treatment. These findings suggest that DXM induces depression- and anxiety-like behavior and suppresses neurogenesis in rats. The current experimental paradigm may serve as an animal model for study on affective effect of cough mixture abuse, rehabilitation treatment options for abusers and the related neurological mechanisms.
    Full-text · Article · May 2015 · Experimental Brain Research
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