Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT<sub>1A</sub>Receptor in Modulating Anxiety-Related Behaviors

Zhang, Jing; Huang, Xinyan; Ye, Min-Li; Luo, Chunxia; Wu, Hai‐Yin; Hu, Yao; Zhou, Qi‐Gang; Wu, Dan-Lian; Zhu, Li‐Juan; Zhu, Dong‐Ya

doi:10.1523/jneurosci.5880-09.2010

Cited by 132 publications

(129 citation statements)

References 39 publications

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“…Western bolt analysis of samples from cultured hippocampal neurons, OHSCs, and hippocampal or hypothalamic tissues of animals was performed as described previously (Zhang et al, 2010). The primary antibodies were as follows: mouse anti-inducible NOS (iNOS; 1:2000; Santa Cruz Biotechnology), rabbit anti-nNOS (1: 1000; Millipore Bioscience Research Reagents), mouse anti-eNOS (1: 2000; Millipore Bioscience Research Reagents), rabbit anti-extracellular signal-regulated kinase (ERK; 1:500; Bioworld Technology), rabbit antiphospho-ERK (1:500; Bioworld Technology), rabbit anti-GR (1:200; Santa Cruz Biotechnology), rabbit anti-MR (1:3000; Santa Cruz Biotechnology), mouse anti-nitrotyrosine (1:3000; Millipore Bioscience Research Reagents), and rabbit anti-corticotrophin-releasing factor (anti-CRF; 1:500; Santa Cruz Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

“…nNOS is enriched throughout the limbic system (Bredt et al, 1991), an area important in emotional behaviors. A number of studies have shown that nNOS has significant implications for the psychiatric disorders characterized by depression (Zhou and Zhu, 2009), anxiety (Zhang et al, 2010), schizophrenia (Shinkai et al, 2002;Reif et al, 2006;O'Donovan et al, 2008), and aggressiveness (Nelson et al, 1995;Chiavegatto et al, 2001). Here, we report that nNOS-mediated GR downregulation in the adult hippocampus underlies the stress-related behavioral effects of glucocorticoids.…”

Section: Introductionmentioning

confidence: 99%

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Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Zhou¹,

Zhu²,

Chen³

et al. 2011

J. Neurosci.

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The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood. We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator. Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor. In turn, hippocampal nNOS-derived nitric oxide (NO) significantly downregulated local glucocorticoid receptor expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO Ϫ )/extracellular signal-regulated kinase signal pathways, and therefore elevated hypothalamic corticotrophin-releasing factor, a peptide that governs the hypothalamic-pituitary-adrenal axis. More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors. In addition, directly delivering ONOO Ϫ donor into hippocampus caused depressive-like behaviors. Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Zhou¹,

Zhu²,

Chen³

et al. 2011

J. Neurosci.

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133

130

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“…In A-D, vs. control; in H-J, vs. vehicle. (22) and is essential for the behavioral effects of nNOS (12), it was appropriate to determine whether CREB is critical for the hippocampal NO-mediated sex difference in affective behaviors. In female hippocampus, the phosphorylated cAMP response element binding protein (pCREB) level was significantly lower than that in males (Fig.…”

Section: Hippocampal No Shortage Contributes To Stress-induced Depresmentioning

confidence: 99%

“…We recently demonstrated that hippocampal nNOS mediates the stress-related depressive behaviors of glucocorticoids (9) and the role of 5-hydroxytryptamine receptor 1A (5-HT1A) receptor in modulating anxiety-related behaviors (12). Evidence from clinical and biological studies indicates that the hippocampus plays an important role in major depression disorder (13).…”

mentioning

confidence: 99%

Hippocampal nitric oxide contributes to sex difference in affective behaviors

Luo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mechanisms underlying the female preponderance in affective disorders are poorly understood. Here we show that hippocampal nitric oxide (NO) plays a role in the sex difference of depressionlike behaviors in rodents. Female mice had substantially lower NO production in the hippocampus and were significantly more likely to display negative affective behaviors than their male littermates. Eliminating the difference in the basal hippocampal NO level between male and female mice mended the sex gap of affective behaviors. Estradiol exerted a positive control on hippocampal NO production via estrogen receptor-β-mediated neuronal NO synthase expression. Thus, low estrogen in the female hippocampus accounts for lower local NO than in the male hippocampus. Although estrogen has important significance in modulating affective behaviors, it is not estrogen but NO in the hippocampus that mediates the sex difference of affective behaviors directly, because hippocampal NO was necessary for the behavioral effects of estradiol, and NO was an independent factor in modulating behaviors. Stress promoted hippocampal NO production in males because of glucocorticoid release, thus leading to local NO excess. In contrast, stress suppressed NO production in females because of decreased estrogen, thereby resulting in hippocampal NO shortage. Whereas activating cAMP response element binding protein (CREB) rescued the depression-like effects of the intrahippocampal NO donor diethylenetriamine/nitric oxide adduct (DETA/NONOate), inactivating CREB abolished the antidepressant-like effects of the intrahippocampal NO donor DETA/NONOate. Our findings suggest a molecular mechanism underlying the sex difference of affective behaviors.A ffective disorders such as depression and anxiety, lifethreatening and highly prevalent stress-related disorders, rank among the top causes of worldwide disease burden and disability (1, 2). It is commonly suggested that a female preponderance in depression and anxiety is universal and substantial. The prevalence of depression and anxiety for women is approximately twice that for men (2-6). Although there are advocates for the implications of hypothalamic-pituitary-adrenal axis hyperactivity in the sex differentiation in some expressions of both depression and anxiety (7), it is not clear what underlies the sex gap in these affective disorders.Neuronal nitric oxide synthase (nNOS) has been implicated in the psychiatric disorders characterized by depression (8, 9), schizophrenia (10), and aggressiveness (11). We recently demonstrated that hippocampal nNOS mediates the stress-related depressive behaviors of glucocorticoids (9) and the role of 5-hydroxytryptamine receptor 1A (5-HT1A) receptor in modulating anxiety-related behaviors (12). Evidence from clinical and biological studies indicates that the hippocampus plays an important role in major depression disorder (13). We found that chronic mild stress (CMS) increased hippocampal NO production by nNOS in male mice (6-9). In contrast, CMS diminished hippocampal NO prod...

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“…Primary neurons were isolated from the hippocampus of mouse embryos at embryonic day 15 (E15), as previously described (Zhang et al., 2010). Cultures were maintained in neurobasal media supplemented with B27, penicillin, streptomycin, and L‐glutamine.…”

Section: Methodsmentioning

confidence: 99%

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

et al. 2018

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SummaryIn neurons, increased protein–protein interactions between neuronal nitric oxide synthase (nNOS) and its carboxy‐terminal PDZ ligand (CAPON) contribute to excitotoxicity and abnormal dendritic spine development, both of which are involved in the development of Alzheimer's disease. In models of Alzheimer's disease, increased nNOS–CAPON interaction was detected after treatment with amyloid‐β in vitro, and a similar change was found in the hippocampus of APP/PS1 mice (a transgenic mouse model of Alzheimer's disease), compared with age‐matched background mice in vivo. After blocking the nNOS–CAPON interaction, memory was rescued in 4‐month‐old APP/PS1 mice, and dendritic impairments were ameliorated both in vivo and in vitro. Furthermore, we demonstrated that S‐nitrosylation of Dexras1 and inhibition of the ERK–CREB–BDNF pathway might be downstream of the nNOS–CAPON interaction.

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Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT_1AReceptor in Modulating Anxiety-Related Behaviors

Cited by 132 publications

References 39 publications

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Hippocampal nitric oxide contributes to sex difference in affective behaviors

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

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Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT1AReceptor in Modulating Anxiety-Related Behaviors

Cited by 132 publications

References 39 publications

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Hippocampal nitric oxide contributes to sex difference in affective behaviors

nNOS–CAPON interaction mediates amyloid‐β‐induced neurotoxicity, especially in the early stages

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Neuronal Nitric Oxide Synthase Alteration Accounts for the Role of 5-HT_1AReceptor in Modulating Anxiety-Related Behaviors