Modulation of Hippocampal GABAergic Neurotransmission and Gephyrin Levels by Dihydromyricetin Improves Anxiety

Silva, Joshua; Shao, Amy S.; Shen, Yi; Davies, Daryl L.; Olsen, Richard W.; Holschneider, Daniel P.; Shao, Xuesi M.; Liang, Jing

doi:10.3389/fphar.2020.01008

Cited by 11 publications

(17 citation statements)

References 72 publications

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“…Finally, GABAergic markers correlated with anxiety-like behaviors exclusively, and were again stronger correlated in males than females. Such changes in the GABAergic system and their link to anxiety-like behaviors are consistent with previous finding, where reduced GPHN levels in the hippocampus are proposed to contribute to anxiety-like phenotype [79, 80]. Similarly, loss of GAD67 function in particular in SST cells is proposed to contribute to anxiety-like phenotype[81] and reduced levels of GAD are reported in human MDD with comorbid anxiety disorders[82, 83].…”

Section: Discussionsupporting

confidence: 89%

Dynamic behavioral and molecular changes induced by chronic stress exposure in mice

Chatterjee

Knoch

et al. 2021

Preprint

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Depression is a leading cause of disabilities around the world, and the underlying mechanisms involved in its pathophysiology are broad and complex. Exposure to chronic stress is a risk factor for developing depressive-symptoms and contributes to cellular and molecular changes precipitating the emergence of symptoms. In the brain, excitatory neurons, inhibitory interneurons and supporting astroglial cells are all sensitive to chronic stress exposure and are known to be impaired in depression. Using an animal model of chronic stress, we assessed the impact of variable durations of chronic stress on the emergence of behavioral deficits and associated molecular changes in the prefrontal cortex (PFC), brain region highly sensitive to stress and impaired in depression. Mice were exposed to up to 35 days of chronic restraint stress and were assessed weekly on behavioral tests measuring anxiety and anhedonia. PFC Protein and RNA levels of specific markers of excitatory, inhibitory synapses and astroglia were quantified using western blot and qPCR, respectively. Correlation and integrative network analyses were used to investigated the impact of chronic stress on the different compartments. Results showed that chronic stress induces anxiety-like behaviors within 7 days, while anhedonia-like behaviors were observed only after 35 days. At the molecular level, alterations of many markers were observed, in particular with longer exposure to chronic stress. Finally, correlation analyses and integrative network analyses revealed that male and female mice react differently to chronic stress exposure and that some markers seem to be more correlated to behaviors deficits in males than in females. Our study demonstrate that chronic induces a dynamic changes that can be observed at the behavioral and molecular levels, and that male and female mice, while exhibiting similar symptoms, have different underlying pathologies.

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Section: Discussionsupporting

confidence: 89%

Dynamic behavioral and molecular changes induced by chronic stress exposure in mice

Chatterjee

Knoch

et al. 2021

Preprint

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“…Mounting evidence has indicated the critical role of GABA transmission in the progression of anxiety disorder (40). In our previous study, we found that changes in gephyrin expression could re ect changes in GABA A R amount and GABAergic function (10,33). Additionally, we found a reduction in GABA A Rmediated extra-synaptic, pre-, and post-synaptic tonic currents in the social isolation anxiety model, which was restored after DHM treatment (33).…”

Section: Discussionmentioning

confidence: 56%

“…In our previous study, we found that changes in gephyrin expression could re ect changes in GABA A R amount and GABAergic function (10,33). Additionally, we found a reduction in GABA A Rmediated extra-synaptic, pre-, and post-synaptic tonic currents in the social isolation anxiety model, which was restored after DHM treatment (33). To elucidate the mechanism in which DHM modulates GABA A Rs in the socially isolated model, gephyrin protein expression was assessed utilizing Western blot.…”

Section: Discussionmentioning

confidence: 98%

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Social Isolation Induces Neuroinflammation And Microglia Overactivation, While Dihydromyricetin Prevents And Improves Them.

Omran

Shao

Watanabe

et al. 2021

Preprint

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Background: Anxiety disorders are the most prevalent mental illnesses in the U.S. and are estimated to consume one-third of the country's mental health treatment cost. Although anxiolytic therapies are available, many patients still exhibit treatment-resistance, relapse, or substantial side effects. Further, due to the COVID-19 pandemic and stay-at-home order, social isolation, fear of the pandemic, and unprecedented times, the incidence of anxiety has dramatically increased. Previously, we have demonstrated dihydromyricetin (DHM), the major bioactive flavonoid extracted from Ampelopsis grossedentata, exhibits anxiolytic properties in a mouse model of social isolation-induced anxiety. Because GABAergic transmission modulates the immune system in addition to the inhibitory signal transmission, we investigated the effects of short-term social isolation on the neuroimmune system.Methods: Eight-week-old male C57BL/6 mice were housed under absolute social isolation for 4 weeks. The anxiety like behaviors after DHM treatment were examined using elevated plus maze and open field behavioral tests. Gephyrin protein expression, microglial profile changes, NF-κB pathway activation, cytokine level, and serum corticosterone were measured. Results: Socially isolated mice showed increased anxiety levels, reduced exploratory behaviors, and reduced gephyrin levels. Also, a dynamic alteration in hippocampal microglia were detected illustrated as a decline in microglia number and overactivation as determined by significant morphological changes including decreases in lacunarity, perimeter, and cell size and increase in cell density. Moreover, social isolation also induced an increase in serum corticosterone level and activation in NF-κB pathway. Notably, DHM treatment counteracted these changes.Conclusion: The results suggest that social isolation contributes to neuroinflammation, while DHM has the ability to restore neuroinflammatory changes induced by anxiety.

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“…Using a mouse model of social isolation stress, we examined social isolation stress induced anxiety levels and the effects of DHM with the elevated plus-maze (EPM) and open field (OF) tests [ 31 – 33 ]. Group-housed control mice (G2 + Veh2) spent 2.31 ± 0.27 (min) of a total 5 min in open arms of the elevated plus-maze (Fig.…”

Section: Resultsmentioning

confidence: 99%

Social isolation induces neuroinflammation and microglia overactivation, while dihydromyricetin prevents and improves them

Omran

Shao

Watanabe

et al. 2022

J Neuroinflammation

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Background Anxiety disorders are the most prevalent mental illnesses in the U.S. and are estimated to consume one-third of the country’s mental health treatment cost. Although anxiolytic therapies are available, many patients still exhibit treatment resistance, relapse, or substantial side effects. Further, due to the COVID-19 pandemic and stay-at-home order, social isolation, fear of the pandemic, and unprecedented times, the incidence of anxiety has dramatically increased. Previously, we have demonstrated dihydromyricetin (DHM), the major bioactive flavonoid extracted from Ampelopsis grossedentata, exhibits anxiolytic properties in a mouse model of social isolation-induced anxiety. Because GABAergic transmission modulates the immune system in addition to the inhibitory signal transmission, we investigated the effects of short-term social isolation on the neuroimmune system. Methods Eight-week-old male C57BL/6 mice were housed under absolute social isolation for 4 weeks. The anxiety-like behaviors after DHM treatment were examined using elevated plus-maze and open field behavioral tests. Gephyrin protein expression, microglial profile changes, NF-κB pathway activation, cytokine level, and serum corticosterone were measured. Results Socially isolated mice showed increased anxiety levels, reduced exploratory behaviors, and reduced gephyrin levels. Also, a dynamic alteration in hippocampal microglia were detected illustrated as a decline in microglia number and overactivation as determined by significant morphological changes including decreases in lacunarity, perimeter, and cell size and increase in cell density. Moreover, social isolation induced an increase in serum corticosterone level and activation in NF-κB pathway. Notably, DHM treatment counteracted these changes. Conclusion The results suggest that social isolation contributes to neuroinflammation, while DHM has the ability to improve neuroinflammation induced by anxiety.

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Modulation of Hippocampal GABAergic Neurotransmission and Gephyrin Levels by Dihydromyricetin Improves Anxiety

Cited by 11 publications

References 72 publications

Dynamic behavioral and molecular changes induced by chronic stress exposure in mice

Dynamic behavioral and molecular changes induced by chronic stress exposure in mice

Social Isolation Induces Neuroinflammation And Microglia Overactivation, While Dihydromyricetin Prevents And Improves Them.

Social isolation induces neuroinflammation and microglia overactivation, while dihydromyricetin prevents and improves them

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