Identity and functional significance of adult neural stem cells

Within the adult CNS, neural stem and progenitor cells continue to generate new neurons. However the identity of adult neural stem cells, as well as the functional significance of the neurons they produce has been unclear. Previous studies have suggested that GFAP-positive astrocytes can generate neurons in the adult CNS, however the extent to which these cells contribute to constitutive neurogenesis was unknown. Moreover, the idea that differentiated astrocytes could possess neural stem cell properties has been controversial. Using a combination of transgenic strategies, we tested the hypothesis that GFAP-expressing cells are the predominant neural stem cell in the adult mammalian forebrain. We further examined the behavioral and physiological consequences of preventing neurogenesis. Transgenically targeted and selective ablation of actively dividing GFAP-positive cells prevented the addition of new neurons, suggesting that these cells are required for neurogenesis. We next employed a fate mapping strategy using Cre/loxP mediated recombination to examine the fate of GFAP-positive neural progenitor cells. An overwhelming majority of newly generated neurons in the adult CNS were found to be derived from a GFAP-expressing neural precursor. These GFAP-expressing neural progenitor cells exhibit distinctive morphological and biochemical properties, distinguishing them from non-dividing GFAP-positive astrocytes. We next examined the functional consequences of preventing neurogenesis and found no deficit in hippocampal dependent fear conditioning, however long term potentiation in the hippocampus was abolished, suggesting that young neurons generated in the adult CNS participate in synaptic plasticity. Taken together, these results indicate that the predominant neural stem cell in the adult mammalian forebrain expresses GFAP, and that ablation of GFAP-positive cells effectively stops neurogenesis resulting in impaired hippocampal function.