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The Journal of Neuroscience, February 27, 2008, 28(9):2231-2241; doi:10.1523/JNEUROSCI.3574-07.2008

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Development/Plasticity/Repair
Ciliary Neurotrophic Factor Mediates Dopamine D₂ Receptor-Induced CNS Neurogenesis in Adult Mice

Peng Yang, Sheila A. Arnold, Agata Habas, Michal Hetman, and Theo Hagg

Kentucky Spinal Cord Injury Research Center and Departments of Neurological Surgery and of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40292

Correspondence should be addressed to Dr. Theo Hagg, Kentucky Spinal Cord Injury Research Center, 511 South Floyd Street, MDR Room 616, Louisville, KY 40292. Email: theo.hagg{at}louisville.edu

Neurogenesis continues in the adult forebrain subventricular zone (SVZ) and the dentate gyrus of the hippocampal formation. Degeneration of dopaminergic projections in Parkinson's disease and animals reduces, whereas ciliary neurotrophic factor (CNTF) promotes, neurogenesis. We tested whether the dopaminergic system promotes neurogenesis through CNTF. Astrocytes of the SVZ and dentate gyrus expressed CNTF and were close to dopaminergic terminals. Dopaminergic denervation in adult mice reduced CNTF mRNA by 60%, whereas systemic treatment with the D₂ agonist quinpirole increased CNTF mRNA in the SVZ and hippocampal formation, and in cultured astrocytes by 1.5–5 fold. The effect of quinpirole in vitro was blocked by the D₂ antagonist eticlopride and did not cause astroglial proliferation or hypertrophy. Systemic quinpirole injections increased proliferation in wild-type mice by 25–75% but not in CNTF^–/– littermates or in the SVZ of mice infused with CNTF antibodies. Quinpirole increased the number of neuroblasts in wild-type but not in CNTF^–/– littermates. Neurogenesis was reduced by 20% in CNTF^–/– mice, confirming the endogenous role of CNTF. Nigrostriatal denervation did not affect SVZ proliferation in CNTF^–/– mice, suggesting that the dopaminergic innervation normally regulates neurogenesis through CNTF. Quinpirole acted on postsynaptic receptors as it reversed the reduced proliferation seen after dopaminergic denervation in wild-type mice. Thus, CNTF mediates dopaminergic innervation- and D₂ receptor-induced neurogenesis in the adult forebrain. Because CNTF is predominantly expressed in the nervous system, this mechanism and the ability to pharmacologically modulate it have implications for Parkinson's disease and cell-replacement therapies for other disorders.

Key words: astrocyte; dopaminergic; neuroblast; quinpirole; subgranular zone; subventricular zone

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Received Aug. 6, 2007; revised Jan. 18, 2008; accepted Jan. 21, 2008.

Correspondence should be addressed to Dr. Theo Hagg, Kentucky Spinal Cord Injury Research Center, 511 South Floyd Street, MDR Room 616, Louisville, KY 40292. Email: theo.hagg{at}louisville.edu

Related articles in J. Neurosci.:

CNTF: A Putative Link between Dopamine D₂ Receptors and Neurogenesis

Mayra Mori, Julius J. Jefferson, Michele Hummel, and David S. Garbe
J. Neurosci. 2008 28: 5867-5869. [Full Text]  

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				G. C. O'Keeffe, P. Tyers, D. Aarsland, J. W. Dalley, R. A. Barker, and M. A. Caldwell Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF PNAS, May 26, 2009; 106(21): 8754 - 8759. [Abstract] [Full Text] [PDF]

				T. Hagg From Neurotransmitters to Neurotrophic Factors to Neurogenesis Neuroscientist, February 1, 2009; 15(1): 20 - 27. [Abstract] [PDF]

				M. A. Mena and J. Garcia de Yebenes Glial Cells as Players in Parkinsonism: The "Good," the "Bad," and the "Mysterious" Glia Neuroscientist, December 1, 2008; 14(6): 544 - 560. [Abstract] [PDF]

				M. Mori, J. J. Jefferson, M. Hummel, and D. S. Garbe CNTF: A Putative Link between Dopamine D2 Receptors and Neurogenesis J. Neurosci., June 4, 2008; 28(23): 5867 - 5869. [Full Text] [PDF]

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