Norepinephrine Directly Activates Adult Hippocampal Precursors via β₃-Adrenergic Receptors

Abstract

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 ␤ 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 ␤ 3 -adrenergic receptor agonist in vivo increases the number of proliferating cells in the SGZ. Similarly, systemic injection of the ␤-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 ␤-adrenergic receptors. These findings suggest that the activation of neurogenic precursors and stem cells via ␤ 3 -adrenergic receptors could be a potent mechanism to increase neuronal production, providing a putative target for the development of novel antidepressants.

Homeostatic neurogenesis in the adult hippocampus does not involve amplification of Ascl1high intermediate progenitors

“…This has complicated analysis of the timing of DG neurogenesis, and a clear understanding of the critical steps in the generation of new neurons is still lacking. Canonical Notch signaling and its downstream target Hes5 are restricted in the SGZ of the DG to NSCs 4,48 . Therefore, we used inducible CreER technology and lineage-traced Hes5 + Notchsignaling cells in the adult DG.…”

Hippocampal Telomerase Is Involved in the Modulation of Depressive Behaviors

“…To evaluate the extent of apoptotic and necrotic cells, a live-cell suspension was prepared from the hippocampus of mice using 0.1% papain as described previously (Jhaveri et al, 2010). Cells were harvested and fixed with 70% prechilled ethanol for at least 12 h at Ϫ20°C.…”

The role of the N-methyl-d-aspartate receptor in the proliferation of adult hippocampal neural stem and precursor cells

“…While speculative, it is possible that LTP primes the NSPCs to respond to factors that directly activate proliferation, via paracrine signalling mechanisms. LTP has been shown to initiate the release of many neurotrophins (e.g., brain-derived neurotrophic factor (BDNF), serotonin, norepinephrine, dopamine, and nitric oxide synthase) [54,55] that are known to modulate adult hippocampal neurogenesis [56,57], and could mediate the observed increase in proliferation following LTP. A paracrine signalling mechanism has been proposed to explain the activity-dependent enhancement of neuronal differentiation in a co-culture model made from EGFP-labelled adult NSPCs with neurons and astrocytes isolated from postnatal day 0 (P0) and P1 mice [58].…”