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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 microM) 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 Ca(2+) 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 Ca(2+) 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.
Highlights
Neuronal activity is primarily generated by neurotransmitters and the role of neurotransmitters extends to proliferation and neuronal differentiation (Levitt et al, 1997)
Whereas members of the ␣-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) subclass of ionotropic glutamate receptor antagonists increase the proliferation of neocortical progenitors (Cameron et al, 1995; Cameron et al, 1998), activation of the N-methyl-Daspartate (NMDA) receptor is required for the proliferation of embryonic striatal progenitors (Luk et al, 2003)
NMDA receptor activation promotes the proliferation of hippocampal neural progenitor cells (NPCs) in vitro To control accurately the extent of activation, and determine the detailed molecular mechanisms responsible for NMDA receptor-dependent neurogenesis, we used well-characterized primary cultures of proliferating cells isolated directly from the hippocampi of embryonic day (E)16.5 rats
Summary
Neuronal activity is primarily generated by neurotransmitters and the role of neurotransmitters extends to proliferation and neuronal differentiation (Levitt et al, 1997). The role of glutamate receptor activation in neural development is complex. Whereas members of the ␣-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) subclass of ionotropic glutamate receptor antagonists increase the proliferation of neocortical progenitors (Cameron et al, 1995; Cameron et al, 1998), activation of the N-methyl-Daspartate (NMDA) (but not the AMPA-KA) receptor is required for the proliferation of embryonic striatal progenitors (Luk et al, 2003). Activation of NMDA receptors on proliferating progenitors induces neuronal differentiation of adult-derived neural progenitor cells (NPCs) in vitro (Deisseroth et al, 2004).
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