Dopamine receptor activation promotes adult neurogenesis in an acute Parkinson model
Introduction
Neural stem and progenitor cells are present in the hippocampal dentate gyrus and the subventricular zone (SVZ), where they continuously generate new neurons in the adult brain (Eriksson et al., 1998, Sanai et al., 2004). Cells born in the SVZ migrate through the rostral migratory stream towards the olfactory bulb, where they differentiate and functionally integrate as GABA-ergic and as dopaminergic interneurons (Carleton et al., 2003). Due to their capacity to detour to regions affected by disease processes (e.g. striatal migration in ischemia and dopaminergic lesions, Arvidsson et al., 2002, Winner et al., 2008) these newborn cells are interesting targets for restorative therapies. Unfortunately, the neurogenic system is compromised in brains undergoing degeneration, as decreased proliferation in neurogenic regions was described in PD patient's hippocampus and SVZ (Hoglinger et al., 2004). This demonstrates that PD associated pathology not only has an impact on the degeneration of mature neurons but also influences the generation of neural progenitor populations in the adult brain. Therefore, stimulation of the endogenous stem- and progenitor cell population might be a promising means to restore some of the disease regions in PD. In that context, we and others recently demonstrated that intracerebral infusion of various growth factors induced striatal neuroblast migration toward the dopaminergic depleted striatum (Winner et al., 2008, Cooper and Isacson, 2004, Mohapel et al., 2005).
Dopamine agonists are first line symptomatic drugs for the treatment of PD patients and are deployed in early stages of the disease (Rascol et al., 2000). The therapeutic effects are derived from binding of the dopamine agonists to the postsynaptic dopamine receptor subtypes in the striatum and the reduction of dopamine turnover in presynaptic dopaminergic neurons in the substantia nigra (SN) (Olanow et al., 1998).
During the development of the brain, dopamine receptors (mostly D3) are abundantly expressed in proliferative neuroepithelial zones (Diaz et al., 1997). In the adult brain, dopaminergic fibers contact the transit amplifying C-cells in the SVZ (Hoglinger et al., 2004). Previous data on neurogenesis in 6-OHDA lesioned rats indicated a reduction in proliferation of neural progenitors (Hoglinger et al., 2004, Baker et al., 2004) as well as an increase in dopaminergic neurogenesis in the glomerular layer of the olfactory bulb (Winner et al., 2006). An additional effect of dopamine agonists may be related to their capacity to act on neural stem and progenitor cells and to promote neurogenesis. An increase in SVZ proliferation following dopaminergic stimulation was shown using 7-OH DPAT (7-hydroxy-N,N-di-n-propyl-2-aminotetralin, a putative D3 receptor agonist) and levodopa in unlesioned and dopamine depleted rats (Hoglinger et al., 2004, Van Kampen et al., 2004, O'Keeffe et al., 2009). This effect may be mediated by activation of D2-like receptors on transit amplifying C-cells most likely via the EGF receptor in conjunction with release of EGF in a PKC-dependent manner (Coronas et al., 2004, O'Keeffe et al., 2009) or via ciliary neurotrophic factor dependant mechanisms (Yang et al., 2008). However, as unlesioned mice did not respond similarly to 7-OH DPAT dopaminergic stimulation, there might be species differences (Baker et al., 2005).
Furthermore controversy exists in the in vitro field, most probably due to different paradigms and cell conditions used in these studies: besides demonstrating a stimulatory effect on proliferation (Coronas et al., 2004, Hoglinger et al., 2004), it was shown that interruption of dopaminergic neurotransmission by D2-antagonists also increases proliferation of SVZ-derived neuroblasts, and is speculated to be a SVZ B-cell induced effect (Kippin et al., 2005). Furthermore, using human midbrain precursor cells, 7-OH DPAT stimulation had no effect on the generation of dopaminergic neurons (Milosevic et al., 2007).
The aim of the present study is to investigate if the oral application of a clinically widely used dopamine agonist (PPX) has a modulatory effect on adult neurogenesis in the SVZ/olfactory bulb system in a PD model mimicking a severe dopaminergic striatal deficit. Moreover, we determined the functional consequences of PPX treatment by open field analysis. In addition, we aimed to analyze dopamine receptor (DR) expression of adult neural stem and progenitor (ANPs) cultures in vitro.
Section snippets
Animals
Three-month old male Fischer 344 rats (Charles River Laboratories, Sulzfeld, Germany), weighing 220 to 250 g, were used. For the in vivo experiment, rats (n = 48) were randomly divided into six groups of n = 8 each. Groups were defined by lesion (6-OHDA) and treatment with PPX or PBS as well as by the time point of perfusion immediately after or 4 weeks after the treatment period (Fig. 1, Fig. 2, Fig. 3). All experiments were carried out in accordance with the European Communities Council Directive
Oral application of PPX in naive rats increases SVZ proliferation
To investigate the effect of orally applied PPX on adult neurogenesis in the SVZ/olfactory bulb system, we first determined the consequences of PPX on cell proliferation in the SVZ of naïve rats (Fig. 1A). SVZ proliferation was assessed using two different approaches: i) BrdU was applied over a period of 10 days labeling all cells that were proliferating during that time period, and animals were perfused at the end of the labeling period. ii) PCNA-immunohistochemistry was used to label cells
Discussion
Oral application of the dopamine agonist PPX is able to stimulate SVZ proliferation in naive animals and more importantly in animals with a severe dopaminergic deficit. Our data provide evidence that the PPX-mediated proliferation depends on the continuous presence of PPX as the increased number of mitotic cells in the SVZ is no longer present 4 weeks after withdrawal (see schematic drawing Fig. 5).
PPX treatment not only increases cell proliferation but also increases the total number of new
Statement of conflict of interest
This study was supported in part by a non-restricted grant from Boehringer Ingelheim Pharma GmbH & Co. KG to Jürgen Winkler. Erich Buerger is working for Böhringer Ingelheim Pharma GmbH & Co. KG.
Acknowledgments
This work was supported by grants from the Bavarian State Ministry of Sciences, Research and the Arts, ForNeuroCell grant (BW and JW), Boehringer Ingelheim Pharma GmbH & Co. KG (JW) and the Alexander von Humboldt Foundation (BW). The authors thank Verena May, Zacharias Kohl, Chichung D. Lie, and Fred H. Gage for helpful discussions as well as Donald P. Pizzo and Andrew Chen for excellent technical support.
Specific contributions:
Beate Winner, Jürgen Winkler: design, analysis, and preparation of
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Current address: Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1099, USA.