The dentate gyrus (DG) of the mammalian hippocampus is hypothesized to mediate pattern separation-the formation of distinct and orthogonal representations of mnemonic information-and also undergoes neurogenesis throughout life. How neurogenesis contributes to hippocampal function is largely unknown. Using adult mice in which hippocampal neurogenesis was ablated, we found specific impairments in spatial discrimination with two behavioral assays: (i) a spatial navigation radial arm maze task and (ii) a spatial, but non-navigable, task in the mouse touch screen. Mice with ablated neurogenesis were impaired when stimuli were presented with little spatial separation, but not when stimuli were more widely separated in space. Thus, newborn neurons may be necessary for normal pattern separation function in the DG of adult mice.

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A reduction in dopaminergic innervation of the subventricular zone (SVZ) is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson's disease (PD). Here, we show that this effect involves EGF, but not FGF2. In particular, we demonstrate that dopamine increases the proliferation of SVZ-derived cells by releasing EGF in a PKC-dependent manner in vitro and that activation of the EGF receptor (EGFR) is required for this effect. We also show that dopamine selectively expands the GFAP ؉ multipotent stem cell population in vitro by promoting their self-renewal. Furthermore, in vivo dopamine depletion leads to a decrease in precursor cell proliferation in the SVZ concomitant with a reduction in local EGF production, which is reversed through the administration of the dopamine precursor levodopa (L-DOPA). Finally, we show that EGFR ؉ cells are depleted in the SVZ of human PD patients compared with age-matched controls. We have therefore demonstrated a unique role for EGF as a mediator of dopamine-induced precursor cell proliferation in the SVZ, which has potential implications for future therapies in PD.T he ability of neural stem and progenitor cells in the adult brain to continually proliferate and generate neuronal precursors is of great significance, because manipulation of this endogenous process may stimulate the replacement of cells lost as a consequence of disease. In the adult mammalian brain, the subventricular zone (SVZ) lining the lateral ventricles is 1 of the 2 primary sites of adult neurogenesis (1, 2), and it is in this niche that the first step in the process of neurogenesis (proliferation) occurs, involving neural stem cells (B cells), that proliferate slowly, giving rise to transitamplifying progenitor cells (C cells) (3). Several locally-acting diffusible molecules, such as EGF, control proliferation in the SVZ (4-7). EGF influences SVZ expansion by binding to the EGF receptor (EGFR) that is present on ''activated B cells'' and rapidly dividing C cells (8).The adult SVZ is innervated by dopaminergic fibers that originate in the substantia nigra (9, 10). These dopaminergic projections extending to the SVZ, predominantly contact the C cells and regulate their proliferative capacity (9). Thus in Parkinson's disease (PD), a dramatic reduction in SVZ precursor cell proliferation occurs as a consequence of dopamine depletion. However, the mechanism by which this occurs is unknown, but given that both dopamine and EGF receptors are coexpressed on the C cell, we sought to investigate the hypothesis that EGF was critical to this process. Using a range of in vitro and in vivo studies, we have now shown that dopamine stimulates the release of EGF from cells in the SVZ, which in turn acts on the EGFR to promote proliferation, and that EGFR expression in the SVZ is significantly depleted in PD patients. ResultsAdult SVZ-derived neural precursor cells (NPCs) displayed clear colocalization for the high-affinity dopamine receptor, the D2-like (D2L) receptor, and the EGFR...

Adult neurogenesis mainly occurs in two brain regions, the subventricular zone and the dentate gyrus (DG) of the hippocampus. Neuropeptide Y (NPY) is widely expressed throughout the brain and is known to enhance in vitro hippocampal cell proliferation. Mice lacking either NPY or the Y1 receptor display lower levels of cell proliferation, thereby suggesting a role for NPY in basal in vivo neurogenesis. Here, we investigated whether exogenous NPY stimulates DG progenitors proliferation in vivo. We show that intracerebroventricular administration of NPY increases DG cell proliferation and promotes neuronal differentiation in C57BL/6 adult mice. In these mice, the proliferative effect of NPY is mediated by the Y1 and not the Y2 receptor, as a Y1 ([Leu(31) ,Pro(34) ]), but not a Y2 (NPY(3-36) ), receptor agonist enhanced proliferation. In addition, no NPY-induced DG cellular proliferation is observed following NPY injection when coadministered with a Y1 antagonist or in the Y1 receptor knockout mouse. These results are in line with data obtained in Y1(-/-) mice, demonstrating that NPY regulates in vivo hippocampal neurogenesis. © 2010 Wiley-Liss, Inc.