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Toll-like receptors modulate adult hippocampal neurogenesis


Neurogenesis — the formation of new neurons in the adult brain — is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes1. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila2 and innate immune activity in mammals3,4, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCα/β-dependent activation of the NF-κB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.

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Figure 1: Impaired neurogenesis in TLR2-deficient mice.
Figure 2: Activation of TLR2 on NPCs increases their neuronal differentiation in vitro.
Figure 3: Activation of TLR2 on NPCs is MyD88- and NFkB-dependent.
Figure 4: TLR4 involvement in adult neurogenesis.
Figure 5: Adult hippocampal neurogenesis is TLR4- and MyD88-dependent.

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We thank Prof. Akira, Dr Uematsu and Prof. Irun Cohen for the TLR-deficient mice, and Dr Stefan Jung for the CX3CR1GFP mice. We thank Shelley Schwarzbaum and Shirley R. Smith for editing, and Shifra Ben-Dor for bioinformatical assistance. M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. This study was supported, in part, by an NRSAD award and by a research grant from Mr and Mrs Richard D. Siegal.

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A.R. and R.S. designed and performed the experiments, analysed the data and took a key part in writing the manuscript. A.L. contributed to the experimental work and data analysis. Y.Z. contributed to the experimental discussions and progenitor purifications. A.R. and R.L. helped with experimental work.

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Correspondence to Michal Schwartz.

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The authors declare no competing financial interests.

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Supplementary Figures S1, S2, S3, S4 and Table S1 (PDF 392 kb)

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Rolls, A., Shechter, R., London, A. et al. Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9, 1081–1088 (2007).

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