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The Journal of Neuroscience, April 23, 2008, 28(17):4488-4500; doi:10.1523/JNEUROSCI.4721-07.2008

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Development/Plasticity/Repair
Tonic Activation of CXC Chemokine Receptor 4 in Immature Granule Cells Supports Neurogenesis in the Adult Dentate Gyrus

Angela Kolodziej,¹ Stefan Schulz,² Alice Guyon,³ Dai-Fei Wu,¹ Manuela Pfeiffer,¹ Veysel Odemis,⁴ Volker Höllt,¹ and Ralf Stumm¹

¹Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany, ²Insitut für Pharmakologie und Toxikologie, Friedrich-Schiller-University, 07743 Jena, Germany, ³Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia Antipolis–Centre National de la Recherche Scientifique, 06560 Valbonne, France, and ⁴Institut für Anatomie, University of Leipzig, 04103 Leipzig, Germany

Correspondence should be addressed to Dr. Ralf Stumm, Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-Universität Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. Email: ralf.stumm{at}medizin.uni-magdeburg.de

Stromal-cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) play a well-established role during embryonic development of dentate gyrus granule cells. However, little is known about the regulation and function of CXCR4 in the postnatal dentate gyrus. Here, we identify a striking mismatch between intense CXCR4 mRNA and limited CXCR4 protein expression in adult rat subgranular layer (SGL) neurons. We demonstrate that CXCR4 protein expression in SGL neurons is progressively lost during postnatal day 15 (P15) to P21. This loss of CXCR4 protein expression was paralleled by a reduction in the number of SDF-1-responsive SGL neurons and a massive upregulation of SDF-1 mRNA in granule cells. Intraventricular infusion of the CXCR4-antagonist AMD3100 dramatically increased CXCR4 protein expression in SGL neurons, suggesting that CXCR4 is tonically activated and downregulated by endogenous SDF-1. Infusion of AMD3100 also facilitated detection of CXCR4 protein in bromodeoxyuridine-, nestin-, and doublecortin-labeled cells and showed that the vast majority of adult-born granule cells transiently expressed CXCR4. Chronic AMD3100 administration impaired formation of new granule cells as well as neurogenesis-dependent long-term recognition of novel objects. Therefore, our findings suggest that tonic activation of CXCR4 in newly formed granule cells by endogenous SDF-1 is essential for neurogenesis-dependent long-term memory in the adult hippocampus.

Key words: CXCL12; internalization; Akt; desensitization; hippocampus; memory; neurogenesis

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Received July 13, 2007; revised Feb. 15, 2007; accepted Feb. 25, 2008.

Correspondence should be addressed to Dr. Ralf Stumm, Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-Universität Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. Email: ralf.stumm{at}medizin.uni-magdeburg.de

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