Transient elevation of adult hippocampal neurogenesis after dopamine depletion

Abstract

Degeneration of the midbrain dopaminergic neurons during Parkinson's disease (PD) may affect remote regions of the brain that are innervated by the projections of these neurons. The dentate gyrus (DG), a site of continuous production of new neurons in the adult hippocampus, receives dopaminergic inputs from the neurons of the substantia nigra (SN). Thus, depletion of the SN neurons during disease or in experimental settings may directly affect adult hippocampal neurogenesis. We show that experimental ablation of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydopyridine (MPTP) mouse model of PD results in a transient increase in cell division in the subgranular zone (SGZ) of the DG. This increase is evident for the amplifying neural progenitors and for their postmitotic progeny; our results also indicate that MPTP treatment affects division of the normally quiescent stem cells in the SGZ. We also show that l-DOPA, used in the clinical treatment of PD, while attenuating the MPTP-induced death of dopaminergic neurons, does not alter the effect of MPTP on cell division in the DG. Our results suggest that a decrease in dopaminergic signaling in the hippocampus leads to a transient activation of stem and progenitor cells in the DG.

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.