The Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.
J Neurosci. 2010 Feb 17;30(7):2795-806. doi: 10.1523/JNEUROSCI.3780-09.2010.
Adult hippocampal neurogenesis is a critical form of cellular plasticity that is greatly influenced by neural activity. Among the neurotransmitters that are widely implicated in regulating this process are serotonin and norepinephrine, levels of which are modulated by stress, depression and clinical antidepressants. However, studies to date have failed to address a direct role for either neurotransmitter in regulating hippocampal precursor activity. Here we show that norepinephrine but not serotonin directly activates self-renewing and multipotent neural precursors, including stem cells, from the hippocampus of adult mice. Mechanistically, we provide evidence that beta(3)-adrenergic receptors, which are preferentially expressed on a Hes5-expressing precursor population in the subgranular zone (SGZ), mediate this norepinephrine-dependent activation. Moreover, intrahippocampal injection of a selective beta(3)-adrenergic receptor agonist in vivo increases the number of proliferating cells in the SGZ. Similarly, systemic injection of the beta-adrenergic receptor agonist isoproterenol not only results in enhancement of proliferation in the SGZ but also leads to an increase in the percentage of nestin/glial fibrillary acidic protein double-positive neural precursors in vivo. Finally, using a novel ex vivo "slice-sphere" assay that maintains an intact neurogenic niche, we demonstrate that antidepressants that selectively block the reuptake of norepinephrine, but not serotonin, robustly increase hippocampal precursor activity via beta-adrenergic receptors. These findings suggest that the activation of neurogenic precursors and stem cells via beta(3)-adrenergic receptors could be a potent mechanism to increase neuronal production, providing a putative target for the development of novel antidepressants.
成年海马神经发生是一种关键的细胞可塑性形式，它受到神经活动的极大影响。在广泛涉及调节这一过程的神经递质中，包括血清素和去甲肾上腺素，它们的水平受到压力、抑郁和临床抗抑郁药的调节。然而，迄今为止的研究未能确定这两种神经递质在调节海马前体细胞活性方面的直接作用。在这里，我们表明去甲肾上腺素而非血清素直接激活来自成年小鼠海马的自我更新和多能神经前体细胞，包括干细胞。从机制上讲，我们提供的证据表明，β3-肾上腺素能受体优先表达在颗粒下区（SGZ）中表达 Hes5 的前体细胞群上，介导这种去甲肾上腺素依赖性激活。此外，体内海马内注射选择性β3-肾上腺素能受体激动剂可增加 SGZ 中增殖细胞的数量。同样，系统注射β-肾上腺素能受体激动剂异丙肾上腺素不仅导致 SGZ 中增殖增强，而且导致体内巢蛋白/胶质纤维酸性蛋白双阳性神经前体细胞的百分比增加。最后，使用一种新颖的体外“切片球体”测定法，该方法维持完整的神经发生龛，我们证明选择性阻断去甲肾上腺素再摄取而不是血清素再摄取的抗抑郁药通过β-肾上腺素能受体强烈增加海马前体细胞活性。这些发现表明，通过β3-肾上腺素能受体激活神经发生前体细胞和干细胞可能是增加神经元产生的有效机制，为开发新型抗抑郁药提供了潜在靶点。
