Dataset Information

NNOS-CAPON blockers produce anxiolytic effects by promoting synaptogenesis in chronic stress-induced animal models of anxiety.

ABSTRACT:

Background and purpose

Anxiety disorder is a common mental health disorder. However, there are few safe and fast-acting anxiolytic drugs available that can treat anxiety disorder. We previously demonstrated that the interaction of neuronal NOS (nNOS) with its carboxy-terminal PDZ ligand (CAPON) is involved in regulating anxiety-related behaviours. Here, we further investigated the anxiolytic effects of nNOS-CAPON disruptors in chronic stress-induced anxiety in animals.

Experimental approach

Mice were intravenously treated with nNOS-CAPON disruptors, ZLc-002 or Tat-CAPON12C, at the last week of chronic mild stress (CMS) exposure. We also infused corticosterone (CORT) into the hippocampus of mice to model anxiety behaviours and also delivered ZLc-002 or Tat-CAPON12C on the last week of chronic CORT treatment via pre-implanted cannula. Anxiety-related behaviours were examined using elevated plus maze, open field, novelty-suppressed feeding and light-dark (LD) tests. The level of nNOS-CAPON interaction was determined by co-immunoprecipitation (CO-IP) and proximity ligation assay (PLA). The neural mechanisms underlying the behavioural effects of nNOS-CAPON uncoupling in anxiety animal models were assessed by western blot, immunofluorescence and Golgi-Cox staining.

Key results

ZLc-002 and Tat-CAPON12C reversed CMS- or CORT-induced anxiety-related behaviours. ZLc-002 and Tat-CAPON12C increased synaptogenesis along with improved dendritic remodelling in CMS mice or CORT-treated cultured neurons. Meanwhile, blocking nNOS-CAPON interaction significantly activated the cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) pathway, which is associated with synaptic plasticity.

Conclusion and implications

Collectively, these results provide evidence for the anxiolytic effects of nNOS-CAPON uncouplers and their underlying mechanisms in anxiety disorders.

SUBMITTER: Zhu LJ

PROVIDER: S-EPMC7393190 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Adult hippocampal neurogenesis and synaptic plasticity are necessary for the behavioral response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine, but the molecular mechanisms underlying these effects are only partially understood. Methods: Anxiety and depressive-like behaviors in mice were developed by chronic mild stress (CMS) or chronic corticosterone (CORT) treatment. Pharmacological and genetic approaches were used to investigate the role of the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction in behavioral and neuroplasticity effects of serotoninergic system. Molecular biological and morphological studies were performed to examine the mechanisms underlying the behavioral effects of nNOS-CAPON interaction that modulated by 5-HT1A receptor (5-HT1AR). Results: Fluoxetine prevented chronic stress-induced nNOS-CAPON upregulation and coupling in the dentate gyrus (DG), and promoting nNOS-CAPON association weakened the anxiolytic and antidepressant effects of fluoxetine in stressed mice. The chronic fluoxetine elevated 5-HT and 5HT1AR agonist 8-OH-DPAT decreased the expression and binding of nNOS with CAPON, whereas 5-HT1AR antagonist NAN-190 had the opposite effects. Importantly, augmenting nNOS-CAPON binding neutralized 8-OH-DPAT-upregulated spine density of DG granule cells and well-characterized synaptic-related proteins, including brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal regulated kinase (ERK), cAMP-response element binding protein (CREB), and synapsin in the DG and abolished the anxiolytic and antidepressant-like effects of 8-OH-DPAT. In contrast, dissociation of nNOS from CAPON rescued the effects of NAN-190 on behavior and neuroplasticity. Conclusion: Taken together, our results indicated that fluoxetine modifies mood behaviors and hippocampal neuroplasticity by disrupting the nNOS-CAPON interaction that links postsynaptic 5-HT1AR activation.