Editors' ChoiceNeuroscience

Is NO a Cause for Depression?

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Science Signaling  04 Sep 2012:
Vol. 5, Issue 240, pp. ec228
DOI: 10.1126/scisignal.2003560

Depression and anxiety are more common in women than in men and have been related to changes that occur in the abundance of the sex hormone estrogen. Noting that nitric oxide (NO) and the enzyme responsible for its synthesis in the brain (nNOS) have been associated with stress responses and mood disorders, Hu et al. explored differences in NO and nNOS in the hippocampi of male and female mice. Male mice had more NO and spent less time immobile in two different tests for depressive behaviors than their female littermates. Intrahippocampal injection of an NO donor into ovariectomized females eliminated the behavior differences in the two tests between males and females; however, dose was critical, with low doses reducing immobility and high doses increasing the time spent immobile. Compared with male mice, females had less E2 estrogen in the hippocampi, and E2 treatment increased the abundance of nNOS in an estrogen receptor β (ERβ)–dependent manner, both in culture and in vivo. E2 or administration of an ERβ agonist reduced the amount of time that ovariectomized mice were immobile in the behavior tests, a reduction that was abolished by treatment with an nNOS inhibitor, an NO scavenger, or an inhibitor of the NO-activated enzyme guanylyl cyclase, as well as in nNOS-knockout mice. Thus, an estrogen-dependent difference in NO signaling appears to contribute to increased depressive behaviors in female mice. However, excess NO signaling initiated by introduction of an NO donor in the hippocampi of both males and females also increased depressive behavior in the two tests. The activity of the transcription factor CREB (as assessed by its phosphorylation status) was higher in hippocampi from male mice. Introduction of an NO donor into the hippocampi of ovariectomized female mice caused a dose-dependent change in the phosphorylation of CREB, with low doses increasing its phosphorylation and high doses decreasing its phosphorylation. CREB phosphorylation also correlated with E2 during the estrous cycle. In females, doses of the NO donor that increased CREB phosphorylation decreased immobile time in the behavior tests, an effect that was blocked by lentiviral injection of a dominant-negative CREB. In contrast, increased CREB phosphorylation was associated with increased immobile time (increased depressive behavior) in males. Thus, the amount of NO signaling appears to be a critical determinant of affective behavior, with too much or too little causing depressive-like behaviors in mice.

Y. Hu, D.-L. Wu, C.-X. Luo, L.-J. Zhu, J. Zhang, H.-Y. Wu, D.-Y. Zhu, Hippocampal nitric oxide contributes to sex difference in affective behaviors. Proc. Natl. Acad. Sci. U.S.A. 109, 14224–14229 (2012). [Abstract][Full Text]

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