ORCID Profile
0000-0002-2539-366X
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Society for Neuroscience
Date: 20-01-2010
DOI: 10.1523/JNEUROSCI.2309-09.2010
Abstract: Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippoc al neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. α 2 -Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of α 2 -adrenoceptors on adult hippoc al neurogenesis. Our results indicate that α 2 -adrenoceptor agonists, clonidine and guanabenz, decrease adult hippoc al neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine β-hydroxylase knock-out ( Dbh −/− ) mice lacking norepinephrine, supporting a role for α 2 -heteroceptors on progenitor cells, rather than α 2 -autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippoc al progenitors in vitro express all the α 2 -adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of α 2 -adrenoceptor stimulation on progenitors. Furthermore, coadministration of the α 2 -adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippoc al progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that α 2 -adrenoceptors, expressed by progenitor cells, decrease adult hippoc al neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants.
Publisher: Public Library of Science (PLoS)
Date: 12-06-2014
Publisher: Society for Neuroscience
Date: 17-02-2010
DOI: 10.1523/JNEUROSCI.3780-09.2010
Abstract: Adult hippoc al 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 hippoc al precursor activity. Here we show that norepinephrine but not serotonin directly activates self-renewing and multipotent neural precursors, including stem cells, from the hippoc us of adult mice. Mechanistically, we provide evidence that β 3 -adrenergic receptors, which are preferentially expressed on a Hes5-expressing precursor population in the subgranular zone (SGZ), mediate this norepinephrine-dependent activation. Moreover, intrahippoc al injection of a selective β 3 -adrenergic receptor agonist in vivo increases the number of proliferating cells in the SGZ. Similarly, systemic injection of the β-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 hippoc al precursor activity via β-adrenergic receptors. These findings suggest that the activation of neurogenic precursors and stem cells via β 3 -adrenergic receptors could be a potent mechanism to increase neuronal production, providing a putative target for the development of novel antidepressants.
No related grants have been discovered for Swananda Marathe.