Abstract
While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g., the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX), and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2′-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 h after a 14-days-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and Neuronal Nuclei (NeuN) 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-days DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active and quiescent neurogenic niches, might be related to the proportional higher D3 receptor affinity of PPX, non-dopaminergic effects of PPX, or altered motor behavior.
Highlights
In order to investigate the effect of two different DA agonists on neural precursor cells (NPCs) proliferation in the adult dentate gyrus (DG), we compared the density of newborn cells between PPX, ROP, and phosphate buffered saline (PBS)-injected animals
PPX only resulted in an increased number of DCX+ neuroblasts in the dorsal striatum suggesting a specific PPX mediated effect in the mouse forebrain, both for constitutively active and quiescent neurogenic niches
While increasing experimental evidence supports the proneurogenic effect of dopaminergic compounds such as levodopa or DA agonists for enhancing adult neurogenesis in the subventricular zone (SVZ) (Van Kampen et al, 2004; Borta and Hoglinger, 2007; Winner et al, 2009) their role in stimulating adult hippocampal neurogenesis is rather limited
Summary
The generation of new neurons in the adult forebrain persists in the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles throughout the mammalian lifespan (Sanai et al, 2004; Ming and Song, 2005; Spalding et al, 2013), including non-human primates and humans (Eriksson et al, 1998; Ngwenya et al, 2006; Jabes et al, 2010; Spalding et al, 2013). Several extrinsic factors regulate proliferation and survival of neural precursor cells (NPCs) such as growth factors, hormones, and neurotransmitters in the “classical” constitutively active neurogenic niches (Brezun and Daszuta, 1999; Kulkarni et al, 2002). In this regard, the neurotransmitter dopamine (DA) plays a pivotal role (Winner et al, 2006; Berg et al, 2011) since dopaminergic fibers directly target hippocampal and SVZ NPCs (Hoglinger et al, 2004). A postnatal turnover of cells was observed in the human striatum post-mortem (Ernst et al, 2014)
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