<scp>nNOS‐CAPON</scp> blockers produce anxiolytic effects by promoting synaptogenesis in chronic stress‐induced animal models of anxiety

Zhu, Li‐Juan; Shi, Hu-Jiang; Chang, Lei; Zhang, Cheng Cheng; Si, Meng; Li, Na; Zhu, Dong‐Ya

doi:10.1111/bph.15084

Cited by 22 publications

(20 citation statements)

References 64 publications

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“…As expected, the gene levels of TNFα, IL‐1β, and IL‐6 in the hippocampus were appreciably elevated after LSI surgery, which were markedly attenuated by resveratrol. Aside from neuroinflammation, a reduction in the pCREB activation and BDNF expression in the hippocampus also appears to intensify anxiety‐like behaviors 31,60 . Strategies to increase pCREB activity and BDNF expression are expected to provide new approaches for suppression of anxiety.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Chen

Gao

et al. 2021

FASEB j.

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Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety‐related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX−/− mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element‐binding protein (pCREB), and brain‐derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment‐enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL‐1β, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol‐mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX−/− mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety‐related behaviors. This study provides that resveratrol‐mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery‐induced LBP and hippocampus‐related anxiety.

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Section: Discussionmentioning

confidence: 99%

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Chen

Gao

et al. 2021

FASEB j.

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“…Given that synaptogenesis is completed within PND 20 [ 33 ], ELS may interfere with this process. Zhu et al reported that chronic mild stress-induced spine loss in dentate gyrus granule cells [ 34 ]. These findings suggest that complex developmental trauma may lead to the weakening of specific neurotransmitter systems, which resulted in reduced brain uptake of radiotracers in this study.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging

Lee

Park

et al. 2021

IJMS

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Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.

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“…To date, despite preclinical evidence revealing that genetic or pharmacological disruption of nNOS/NOS1AP interactions targeting an intermediate region of the dentate gyrus (and parts of CA3) has anxiolytic effects [ 13 , [68] , [69] , [70] ], there is no study linking NOS1AP to anxiety in humans. Consistent with this lack of clinical association, in the present study overexpression of NOS1AP throughout the dorsal hippocampus did not affect anxiety-related behaviours.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders

et al. 2021

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Background Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. Methods To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes. Findings We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity. Interpretation Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule. Funding This study was funded in part by the DFG, the BMBF, the Academy of Finland, the NIH, the Japanese Society of Clinical Neuropsychopharmacology, the Ministry of Education of the Russian Federation, and the European Community.

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nNOS‐CAPON blockers produce anxiolytic effects by promoting synaptogenesis in chronic stress‐induced animal models of anxiety

Cited by 22 publications

References 64 publications

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging

Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders

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