The role of granulocyte-colony stimulating factor (G-CSF) in the healthy brain: a characterization of G-CSF-deficient mice.
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.
Diederich
Kai
K
Department of Neurology, University of Muenster, 48149 Muenster, Germany. kai.diederich@uni-muenster.de
Sevimli
Sevgi
S
Dörr
Henrike
H
Kösters
Evelin
E
Hoppen
Maike
M
Lewejohann
Lars
L
Klocke
Rainer
R
Minnerup
Jens
J
Knecht
Stefan
S
Nikol
Sigrid
S
Sachser
Norbert
N
Schneider
Armin
A
Gorji
Ali
A
Sommer
Clemens
C
Schäbitz
Wolf-Rüdiger
WR
D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal / Q000502:physiology*; D001703:Biophysics; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016291:Dizocilpine Maleate / Q000378:metabolism; D000089622:Doublecortin Domain Proteins; D004558:Electric Stimulation / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000172:deficiency / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009118:Muscimol / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D009479:Neuropeptides / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D018079:Receptors, GABA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D021641:Recognition, Psychology / Q000502:physiology; D016622:Silver Staining / Q000379:methods; D014316:Tritium / Q000378:metabolism
D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D016179:Granulocyte Colony-Stimulating Factor; D009118:Muscimol; D016291:Dizocilpine Maleate; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine