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The Journal of Neuroscience, September 16, 2009, 29(37):11572-11581; doi:10.1523/JNEUROSCI.0453-09.2009

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Behavioral/Systems/Cognitive
The Role of Granulocyte-Colony Stimulating Factor (G-CSF) in the Healthy Brain: A Characterization of G-CSF-Deficient Mice

Kai Diederich,^1 * Sevgi Sevimli,^1 * Henrike Dörr,⁶ Evelin Kösters,³ Maike Hoppen,¹ Lars Lewejohann,² Rainer Klocke,⁴ Jens Minnerup,¹ Stefan Knecht,¹ Sigrid Nikol,⁴ Norbert Sachser,² Armin Schneider,⁷ Ali Gorji,³ Clemens Sommer,^6 ** and Wolf-Rüdiger Schäbitz^5 **

Department of ¹Neurology and ²Behavioral Biology, and ³Institute of Physiology I, University of Muenster, ⁴Department of Cardiology and Angiology, University Hospital of Muenster, and ⁵Department of Neurology, Evangelisches Krankenhaus Bielefeld and University of Muenster, 48149 Muenster, Germany, ⁶Department of Neuropathology, University of Mainz, 55131 Mainz, Germany, and ⁷Sygnis Bioscience, 69120 Heidelberg, Germany

Correspondence should be addressed to Kai Diederich, Universitätsklinikum Münster, Klinik und Poliklinik für Neurologie, Albert-Schweitzer-Strasse 33, 48149 Muenster, Germany. Email: kai.diederich{at}uni-muenster.de

Granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor that controls proliferation and differentiation of neural stem cells. Although recent studies have begun to explore G-CSF-related mechanisms of action in various disease models, little is known about its function in the healthy brain. In the present study, the effect of G-CSF deficiency on memory formation and motor skills was investigated. The impact of G-CSF deficiency on the structural integrity of the hippocampus was evaluated by analyzing the generation of doublecortin-expressing cells, the amount of bromodeoxyurine-labeled cells, the dendritic complexity in hippocampal neurons, the binding densities of NMDA and GABA_A receptors and the induction of long-term potentiation (LTP). G-CSF deficiency caused a disruption in memory formation and in the development of motor skills. These impairments were associated with reduced ligand binding densities of NMDA receptors in hippocampal subfields CA3 and the dentate gyrus. The reduced excitation was potentiated by increased ligand binding densities of GABA_A receptors resulting in a relative shift in favor of inhibition and impaired behavioral performance. These alterations were accompanied by impaired induction of LTP in the CA1 region. Moreover, G-CSF deficiency led to decreased dendritic complexity in hippocampal neurons in the dentate gyrus and the CA1 region. G-CSF deficiency also caused a reduction of neuronal precursor cells in the dentate gyrus. These findings confirm G-CSF as an essential neurotrophic factor, and point to a role in the proliferation, differentiation and functional integration of neural cells necessary for the structural and functional integrity of the hippocampal formation.

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Received Jan. 28, 2009; revised June 29, 2009; accepted July 23, 2009.

Correspondence should be addressed to Kai Diederich, Universitätsklinikum Münster, Klinik und Poliklinik für Neurologie, Albert-Schweitzer-Strasse 33, 48149 Muenster, Germany. Email: kai.diederich{at}uni-muenster.de

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