Transient elevation of adult hippocampal neurogenesis after dopamine depletion
Introduction
New neurons are continuously generated in the adult mammalian brain (Gage et al., 2008, Lledo et al., 2006, Ming and Song, 2005, Zhao et al., 2008). Persistent neurogenesis is normally restricted to the subventricular zone (SVZ) of the lateral wall of the lateral ventricles, and the dentate gyrus (DG) of the hippocampus. New neurons are produced from neural stem and progenitor cells after a series of division, elimination, differentiation, and maturation events. Each step of this differentiation cascade can be affected by a variety of intrinsic and extrinsic factors, among them neurotransmitters such as dopamine (Lledo et al., 2006, Zhao et al., 2008). Furthermore, adult neurogenesis is strongly affected by aging and disease. Parkinson's disease (PD), in particular, may have a profound effect on adult neurogenesis, with results from both in vitro and in vivo settings indicating that dopamine is a potent regulator of proliferation of neural progenitors (Baker et al., 2004, Borta and Hoglinger, 2007, Dawirs et al., 1998, Freundlieb et al., 2006, Hoglinger et al., 2004, Kippin et al., 2005, O'Keeffe et al., 2009, Peng et al., 2008, Yang et al., 2008). The neurogenic regions of the adult brain are innervated by dopaminergic projections from the substantia nigra (SN) and ventral tegmental area (VTA) (Gasbarri et al., 1997, Gasbarri et al., 1994, Scatton et al., 1980, Swanson, 1982, Verney et al., 1985); therefore, the reduction of the dopamine levels caused by the disease may directly affect the production of new neurons in the SVZ and DG. Given the possible link between production of new neurons and mood disorders and olfaction (Sahay et al., 2007, Warner-Schmidt and Duman, 2006, Zhao et al., 2008), it is conceivable that inadequate neurogenesis in the SVZ and DG may underlie depression and impairment of olfaction which often accompany PD.
The specific cell populations and the stages of the neuronal differentiation cascade affected by dopamine are not known. Moreover, the effect of dopamine on neurogenesis may be complex and this neurotransmitter has been described both as a positive and a negative regulator of neurogenesis and neural stem/progenitor cell proliferation. Dopamine receptor antagonists and dopamine depletion have been reported to reduce cell proliferation in the SVZ and DG of rodents and primates (Baker et al., 2004, Borta and Hoglinger, 2007, Freundlieb et al., 2006, Hoglinger et al., 2004, O'Keeffe et al., 2009, Yang et al., 2008); however, exposure to dopamine antagonists and ablation of dopaminergic neurons have also been reported to induce neural stem/progenitor cell division (Dawirs et al., 1998, Kippin et al., 2005, Peng et al., 2008). The outcome of the changes in the dopamine levels may reflect a differential response of dopamine receptors and transporters to the variations in the neurotransmitter's levels, activation of compensatory mechanisms, specifics of the animal models, as well as the stage of the disease progression.
We here investigated the effect of dopamine depletion on hippocampal neurogenesis in the 1-methyl-4-phenyl-1,2,3,6-tetrahydopyridine (MPTP) animal model of PD (Bove et al., 2005, Jackson-Lewis and Przedborski, 2007). Our results indicate that ablation of dopaminergic neurons leads to a transient elevation of hippocampal neurogenesis and that the destruction of dopaminergic neurons in the SN may be the main cause of this elevation. They further indicate that levodopa (l-DOPA) modulates the effect of the ablation and that both the quiescent and the amplifying populations of neural progenitors in the DG may be the main targets of the changed dopamine levels. These results suggest a stage-dependent effect of dopamine depletion on DG neurogenesis.
Section snippets
Animals
Adult male C57BL/6 mice were used for all experiments (11–15 weeks old at the onset of experiment; purchased from Taconic Farms, Inc., NY). Animals were housed in a standard light- and temperature-controlled environment (12 h light/dark cycle; light on at 7:00 a.m.; t = 21 ± 2°) and access to food and water ad libitum. All procedures were approved by Animal Care and Use Committees of Cold Spring Harbor Laboratory, and the protocols are in accordance with Guidelines for the Use and Treatment of
Neurotoxin MPTP destroys dopaminergic neurons and their fibers
To examine the effect of dopamine innervation on adult hippocampal neurogenesis, we selectively ablated dopaminergic neurons by exposing mice to the neurotoxin MPTP (4 injections of 20 mg/kg MPTP with 2 h intervals, with the control group receiving saline injections) (Bove et al., 2005, Jackson-Lewis and Przedborski, 2007). To characterize the effect of MPTP on dopaminergic neurons and on hippocampal neurogenesis, we analyzed the animals 4, 7, 14, and 30 days after the MPTP treatment, injecting
Discussion
Dopaminergic neurons of the SN and VTA send numerous projections to distant regions of the brain (Gasbarri et al., 1997, Gasbarri et al., 1994, Scatton et al., 1980, Swanson, 1982, Verney et al., 1985); thus, degeneration of the SN dopaminergic neurons, a hallmark of Parkinson's disease, may have profound consequences for these remote regions. In particular, major dopaminergic projections from the midbrain are found in the hippocampal formation and the DG, the site of persistent adult
Acknowledgments
We are grateful to Serge Przedborski (Columbia University) for advice. We thank our lab members Juan Manuel Encinas, Tatyana Michurina and Natalia Peunova for help and advice, Stephen Hearn (CSHL) for help with microscopy, and Lisa Bianco and Jodi Coblentz (CSHL) for their help with the animal studies. This work was supported by The Hartman Foundation for Parkinson's Research, National Institute of Mental Health, National Alliance for Research on Schizophrenia and Depression (NARSAD), Hope for
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