Glutamate as a modulator of embryonic and adult neurogenesis

It has been widely accepted that neurogenesis continues throughout life. Neural stem cells can be found in the ventricular zone of the embryonic and in restricted regions of the adult central nervous system, including subventricular and subgranular zones of the hippocampal dentate gyrus. The network of signaling mechanisms determining whether neural stem cells remain in a proliferative state or differentiate is only partly discovered. Recent advances indicate that glutamate (Glu), the predominant excitatory neurotransmitter in mature neurons, can influence immature neural cell proliferation and differentiation, as well. Despite many similarities, Glu actions on neurogenesis in the developing and adult brain show distinct differences and are far from being clear. Due to alterations of Glu transport mechanisms, extracellular Glu level is high in the embryonic CNS. Glu acts non-synaptically on dividing progenitors either by directly activating ionotropic and/or metabotropic Glu receptors or can influence other cells which are located in the vicinity of proliferating cells and produce molecules regulating neural precursor cell proliferation by other mechanisms. Due to the complexity of signaling pathways and to regional differences in neural precursors, Glu can influence proliferation and neuronal commitment as well, and acts as a positive regulator of neurogenesis. Brain injuries like ischemia, epilepsy or stress lead to severe neuronal death and additionally, influence neurogenesis, as well. Glu homeostasis is altered under these pathological circumstances, implying that therapeutic treatments mediating Glu signaling might be useful to increase neuronal replacement after cell loss in the brain.