Editors' ChoiceNeuroscience

Microglial Messages Modulate Neurogenesis

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Science Signaling  02 Sep 2008:
Vol. 1, Issue 35, pp. ec307
DOI: 10.1126/scisignal.135ec307

Environmental enrichment and increased activity stimulate hippocampal neurogenesis in mice; this effect is diminished in mice lacking presenilin 1 (PS1), which has also been implicated in the pathogenesis of Alzheimer's disease (AD) (see Villeda and Wyss-Coray). Choi et al. found that proliferation of hippocampal neural progenitor cells (NPCs) in response to an enriched environment was attenuated in transgenic mice bearing either of two ubiquitously expressed human PS1 variants associated with early-onset familial AD (FAD) but not in mice ubiquitously expressing wild-type human PS1. Similarly, an increase in the number of granule cells in the dentate gyrus of the hippocampi of highly active “enriched mice” was reduced by the FAD-linked PS1 variants. FAD-linked PS1 variants were also associated with suppression both of enrichment-induced neurogenesis and of an increase in the numbers of hippocampal microglia in highly active enriched mice. The rate of in vitro proliferation of purified hippocampal NPCs expressing FAD-linked PS1 variants did not differ from that of NPCs expressing wild-type human PS1. However, coculture analyses revealed that microglia from mice expressing FAD-linked PS1 variants inhibited the proliferation of NPCs expressing wild-type human PS1. Indeed, conditioned medium from variant-expressing microglia inhibited NPC proliferation and neuronal differentiation. Further, the abundance of various signaling proteins differed in medium from microglia expressing wild-type or variant PS1, as did transcripts in the respective cultured microglia and in hippocampal microglia isolated from the respective transgenic mice. The authors thus conclude that signaling factors derived from microglia are critical to the inhibition of adult hippocampal neurogenesis by FAD-linked PS1 variants.

S. H. Choi, K. Veeraraghavalu, O. Lazarov, S. Marler, R. M. Ransohoff, J. M. Ramirez, S. S. Sisodia, Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron 59, 568-580 (2008). [PubMed]

S. Villeda, T. Wyss-Coray, Microglia—A wrench in the running wheel? Neuron 59, 527-529 (2008). [PubMed]

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