Depletion of norepinephrine decreases the proliferation, but does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus

Abstract

The dentate gyrus region retains the ability to generate neurons throughout adulthood. A few studies have examined the neurotransmitter regulation of adult hippocampal neurogenesis and have shown that this process is regulated by serotonin and glutamate. Given the strong noradrenergic innervation of the adult hippocampus and the ability of norepinephrine to influence proliferation during development, we examined the influence of norepinephrine on adult hippocampal neurogenesis. Our study indicates that depletion of norepinephrine by the selective noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromo benzylamine hydrochloride (DSP-4), results in a 63% reduction in the proliferation of dentate gyrus progenitor cells identified through 5-bromo-2'-deoxyuridine (BrdU) labelling. In contrast, the survival of BrdU-positive cells labelled prior to treatment with DSP-4 is not influenced by norepinephrine depletion. The differentiation of BrdU labelled progenitors into neurons or glia was also not sensitive to noradrenergic depletion. These results indicate that the proliferation, but not the survival or differentiation, of adult hippocampal granule cell progenitors is affected by norepinephrine depletion.

Brain-Derived Neurotrophic Factor and Antidepressant Drugs Have Different But Coordinated Effects on Neuronal Turnover, Proliferation, and Survival in the Adult Dentate Gyrus

“…Antidepressant treatment increased neuronal progenitor-cell proliferation to a similar degree in both wild-type mice and in two transgenic strains of mice with reduced BDNF signaling, trkB.T1-overexpressing mice and BDNF ϩ/Ϫ mice. These data indicate that the proliferation phase is not regulated by neurotrophins but is regulated by other effects, most likely involving the increase in extracellular levels of serotonin and norepinephrine (Gould, 1999;Kulkarni et al, 2002;Santarelli et al, 2003). In contrast, our data suggest that the longterm survival on the newly born neurons appears to require functional BDNF signaling (Lee et al, 2002), as has also been reported in vitro (Barnabe-Heider and Miller, 2003).…”

Current perspectives of the roles of the central norepinephrine system in anxiety and depression

“…[81][82][83] Additionally, persistent elevation of circulating corticosteroids can also cause atrophy of other important brain regions for cognitive and emotional processes, such as the prefrontal cortex and amygdala. [84,85] As depletion of central NE leads to a decline in adult hippocampal neurogenesis, [86,87] it is likely that an elevation of NE (e.g., by antidepressants) has an indirect role in regulating BDNF-dependent adult hippocampal neurogenesis. [88] This elevation of BDNF may be an important part of the cellular processes that underlie antidepressant efficacy.…”

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

“…Wood et al, 2001;Berg et al, 2006;Dekeyne et al, 2008;Chanrion et al, 2008;Millan MJ unpublished observations). The notion that inverse agonism is required for enhancing proliferation in the VH is supported by evidence that certain cerebral populations of 5-HT 2C receptors are constitutively active (Berg et al, 2005), including sites tonically inhibitory, through GABAergic interneurones, to ascending dopaminergic or noradrenergic systems that are known to increase cell proliferation (Invernizzi et al, 2007;Hoglinger et al, 2004;Kulkarni et al, 2002;Millan et al, 2008;Aloyo et al, 2009). However, the interpretation of these data is also complicated by the fact that constitutive activity at 5-HT 2C sites is regulated by mRNA editing that differs between brain regions; extensively edited 5-HT 2C receptor isoforms being constitutively silent (Burns et al, 1997;Sanders-Bush et al, 2003).…”