REVIEW
Dopamine and adult neurogenesis

* Andreas Borta and
* Günter U. Höglinger

*
Experimental Neurology, Philipps University, Marburg, Germany

Address correspondence and reprint requests to Günter U. Höglinger, Experimental Neurology, Philipps University, D-35033 Marburg, Germany. E-mail: guenter.hoeglinger@med.uni-marburg.de



Dopamine is an important neurotransmitter implicated in the regulation of mood, motivation and movement. We have reviewed here recent data suggesting that dopamine, in addition to being a neurotransmitter, also plays a role in the regulation of endogenous neurogenesis in the adult mammalian brain. In addition, we approach a highly controversial question: can the adult human brain use neurogenesis to replace the dopaminergic neurones in the substantia nigra that are lost in Parkinson's disease?

The recent discovery that the adult mammalian brain has the potential to generate new neurones and to integrate them into existing circuits has caused a shift in our understanding of how the central nervous system functions in health and disease (Alvarez-Buylla and Lim 2004). It has been consistently demonstrated, in two distinct areas of the forebrain, that mature cells in all neural lineages, including neurones, are generated throughout adulthood. Neuroblasts born in the adult subventricular zone (SVZ), subadjacent to the ependyma lining the lateral ventricles, migrate along the rostral migratory stream to the olfactory bulb, where they become interneurones. Neuroblasts born in the adult subgranular zone (SGZ) of the dentate gyrus migrate into the adjacent granular layer, where they become granular neurones. The constitutive neurogenesis that occurs in the SVZ and SGZ is thought to be of functional importance in olfaction, mood regulation and memory processes (Nilsson et al. 1999; Santarelli et al. 2003; Enwere et al. 2004; Kempermann et al. 2004). The factors that govern the generation, migration, differentiation, integration and survival of new neuroblasts in the SVZ and SGZ include diffusible molecules such as neurotransmitters (Hagg 2005; Lledo and Saghatelyan 2005). It is therefore conceivable that an alteration in brain neurotransmitter levels, as occurs in neurodegenerative diseases, would affect adult neurogenesis in the SVZ and SGZ with yet unknown functional consequences. Inversely, the discovery of adult neurogenesis has raised the hope that the SVZ and SGZ, or other regions of the adult brain, might still have the capacity to generate neuroblasts that can replace the neurones lost through disease.

Parkinson's disease (PD) has received much attention in recent years with regard to adult neurogenesis, as the degenerative process is relatively selective for the dopaminergic nigrostriatal projection. We have evaluated the published evidence indicating that (i) dopamine plays a role in the regulation of constitutive neurogenesis in the adult brain, and that (ii) adult neurogenesis can repair the damaged nigrostriatal dopaminergic system.
Dopaminergic control of adult neurogenesis


The neurotransmitter dopamine contributes to the ontogenesis of the mammalian brain by regulating neural precursor cell proliferation. Dopamine (Voorn et al. 1988; Ohtani et al. 2003) and its receptors (Lidow and Rakic 1995; Diaz et al. 1997) appear early during embryonic development in the highly proliferative germinal zones of the brain. Dopamine receptors are classified as either D1-like (D1 and D5) or D2-like (D2, D3 and D4), according to structural homologies and shared second messenger cascades. Dopamine receptors, particularly of the D3 type, are abundantly expressed during brain development in the germinative neuroepithelial zones actively involved in neurogenesis in most basal forebrain structures, thereby supporting the hypothesis that dopamine plays a role in neurogenesis during brain development (Diaz et al. 1997). Indeed, dopamine has been shown to either activate or inhibit, through D1- and D2-like receptors, respectively, the proliferation of precursor cells in the lateral ganglionic eminence, which is the neuroepithelial precursor of the neostriatum, and in the cortical neuroepithelium, the germinal precursor of the dorsomedial prefrontal cortex in the developing brain (Ohtani et al. 2003; Popolo et al. 2004). Although the effect of dopamine on progenitor cell proliferation is well documented, it is not known whether it acts on neural stem cells. In the adult brain, high levels of D3 receptor expression have been shown to persist in the germinal SVZ (Diaz et al. 1997). As a developmental continuum appears to link embryonic stem cells to adult neural precursor cells in the SVZ and SGZ (Alvarez-Buylla et al. 2001), dopamine may also be implicated in adult neurogenesis in the SVZ.

The anatomical evidence

The adult SVZ has a unique cytoanatomical and functional organization (Doetsch et al. 1997). A specialized type of glial fibrillary acidic protein+ (GFAP+) astrocytes, so-called B-cells, act as stem cells, which means that they have the potential to self-renew and to give rise to astrocytes, oligodendrocytes and neurones (Doetsch et al. 1999). B-cells generate frequently dividing transit-amplifying C-cells, which can be identified by their expression of the receptor for epidermal growth factor (EGFR) (Doetsch et al. 2002; Höglinger et al. 2004). Asymmetric division of C-cells gives rise to polysialic neural cell adhesion molecule+ (PSA-NCAM+)-restricted neural precursors (A-cells), destined to migrate via the rostral migratory stream to the olfactory bulb, where they integrate as interneurones (Luskin 1993).

Immunohistochemical and electron microscopy studies have show that D2-like dopamine receptors are expressed predominately on C-cells, whereas A-cells express both D1- and D2-like receptors (Höglinger et al. 2004). As highly specific antibodies for the individual receptor types are not available at the present time, a more detailed analysis of the receptor distribution has not yet been possible. The distribution described in the adult SVZ (Höglinger et al. 2004), however, is consistent with the predominant expression of D3 receptors (belonging to the D2-like group) on proliferating precursor cells and D1 receptors (belonging to the D1-like group) on migrating neuroblasts, which has been shown by in situ hybridization in the embryonic brain (Diaz et al. 1997). Furthermore, immunhistochemical studies and both confocal and electron microscopy (Höglinger et al. 2004) have demonstrated that C-cells in the adult SVZ are embedded in a rich network of dopaminergic afferents that form synapse-like structures (Figs 1a and b). Finally, anterograde tracing studies in non-human primates have demonstrated that the dopaminergic fibers in the SVZ originate, at least in part, in the pars compacta of the substantia nigra (Freundlieb et al. 2006). These anatomical observations support the existence of a nigro-subventricular dopaminergic projection terminating on transit-amplifying C-cells, thus raising the question of its effect on function.
The cell biological evidence

In order to assess the functional effect of dopamine on precursor cells in the SVZ, a series of experiments was performed in neurosphere cultures, a culture system enriched in proliferating neuronal stem cells and early precursor cells (Reynolds and Weiss 1992; Morshead et al. 1994). The expression of EGFR in virtually all cells in neurosphere cultures strongly suggests that most cells in these cultures are C-cells (Fig. 1c). Expression of D1- and D2-like dopamine receptors in neurospheres (Fig. 1c) has been demonstrated by immunhistochemistry and PCR (Coronas et al. 2004; Höglinger et al. 2004; Kippin et al. 2005). Treatment of neurospheres with the D2-like agonists bromocriptine and apomorphine, at concentrations typically used for in vitro experiments and for time periods ranging from 12 h to 3 days, significantly increased cell proliferation, as quantified by the percentage of cells incorporating the thymidine analogue 5-bromo-2'deoxyuridine (BrdU) into their nuclear DNA (Coronas et al. 2004; Höglinger et al. 2004). An effect of these D2-like agonists on the rate of cell death in neurosphere cultures was excluded by TUNEL-staining (Coronas et al. 2004; Höglinger et al. submitted). The effect of bromocriptine and apomorphine on cell proliferation was blocked by the D2-like antagonist sulpiride (Coronas et al. 2004; Höglinger et al. 2004), suggesting that it was indeed mediated via the D2-like receptors. No effect of the D1-like agonist SKF 38393 on cell proliferation has been observed (Höglinger et al. 2004). Dopamine, acting on both D1- and D2-like receptors, reproduced the effect of the D2-like agonists (Höglinger et al. 2004). These observations are consistent with the proliferation-inducing effect of D3 receptor activation as described in neuroblastoma cells (Pilon et al. 1994), and suggest that the activation of D2-like receptors on transit-amplifying C-cells in neurosphere cultures stimulates their proliferation (Fig. 2).

Kippin et al. (2005) reported that a chronic, but not an acute, treatment of adult rats with the D2-like antagonist haloperidol led to an increase in the number of primary neurospheres obtained from the SVZ, and that passaging of primary neurospheres in the presence of either dopamine or the D2-like agonist quinpirole led to the formation of fewer subsequent neurospheres. From these observations they concluded that dopamine inhibits the proliferation of B-cells. However, as no dopamine receptors have been identified by electron microscopy on B-cells in vivo, and as there is no evidence for an alteration of B-cell proliferation by dopamine depletion in vivo (Höglinger et al. 2004), the idea that B-cells are indeed modulated by dopamine remains controversial.

The evidence from integrated in vivo systems

A substantial volume of work has been carried out to assess the effects of dopamine on precursor cell proliferation in the SVZ in vivo. Experimental ablation of the dopaminergic innervation of the forebrain in mice and rats using the neurotoxins MPTP and 6-hydroxydopamine (6-OHDA) has been repeatedly shown to reduce global cell proliferation in the SVZ by 30–45% (Baker et al. 2004; Höglinger et al. 2004; Winner et al. 2006). More detailed analysis showed that this was a result of selective reduction in the proliferation of transit-amplifying C-cells (Höglinger et al. 2004), consistent with the results of the in vitro experiments described above. The inhibition of dopaminergic transmission in adult rats in vivo using the D2-like antagonist haloperidol has led to inconsistent results (Wakade et al. 2002; Kippin et al. 2005). However, systemic treatment of either normal or dopamine-depleted rats with the D2-like agonists ropinirole or 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) significantly increased precursor cell proliferation in the SVZ (Höglinger et al. 2004; Van Kampen et al. 2004). Levodopa also had a significant, although less pronounced, stimulatory effect on SVZ cell proliferation in the dopamine-depleted rats (Höglinger et al. 2004). In unlesioned adult control mice, 7-OH-DPAT did not significantly stimulate SVZ cell proliferation (Baker et al. 2005), perhaps because the dopaminergic stimulation of cell proliferation was already maximal, as dopamine depletion effectively reduced cell proliferation in the SVZ (Baker et al. 2004; Höglinger et al. 2004). Together, these data suggest that in the integrated adult rodent SVZ in vivo, the predominant effect of D2-like receptor activation is the stimulation of C-cell proliferation and, consecutively, the production of migrating neuroblasts (A-cells), whereas dopamine depletion has the opposite effect (Fig. 2).

The fact that there is increased gliogenesis in the striatum of dopamine-depleted rats (Mohapel et al. 2005), mice (Kay and Blum 2000; Mao et al. 2001; Chen et al. 2002, 2004) and primates (Tandéet al. 2006) does not invalidate this conclusion. This phenomenon appears to result from a reaction of gliogenic precursor cells intrinsic to the striatum to neurotoxin-induced neurodegeneration, rather than from the recruitment of neural precursor cells in the SVZ. Within 12 h of MPTP administration in mice (Höglinger et al. unpublished), proliferating cell nuclear antigen-immunoreactive nuclei suggestive of cell proliferation were distributed homogeneously throughout the striatum, as were newborn glial cells in MPTP-treated primates (Tandéet al. 2006), but there was no evidence of a cell density gradient that would be observed if the cells were migrating from the SVZ.

Also in the SGZ of mice, dopaminergic fibres were observed in the vicinity of precursor cells (Höglinger et al. 2004), and precursor cell proliferation was reduced after MPTP treatment. It cannot be concluded, however, on the basis of the scarce data available, that dopamine also regulates precursor cell proliferation in the adult SGZ.