Downregulation of Egr-1 Expression Level via GluN2B Underlies the Antidepressant Effects of Ketamine in a Chronic Unpredictable Stress Animal Model of Depression

Zhang, Weijie; Wang, Hua-hua; Lv, Yidong; Liu, Cai-Cai; Sun, Wenyao; Tian, L.

doi:10.1016/j.neuroscience.2017.12.045

Cited by 33 publications

(15 citation statements)

References 35 publications

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“…Although, no multi-hit related study is reported so far but these observation tally with results reported on single exposure of Poly I:C and LPS ( Kondo et al, 2011 ; Bai et al, 2015 ; Zhang et al, 2015 ; Li et al, 2015 ; Burrows et al, 2016 ; Qiao et al, 2016 ). In our study, the LP+Poly I:C+LPS animals showed severe downregulation of Egr 1 protein and similar to this, chronic stress induced downregulation of Egr 1 was reported by Matsumoto et al (2012) , Okada et al, (2014) , Ieraci et al (2016) and Zhang et al, (2018) . They further suggested that Egr 1 gene downregulation can be related to various neurological disorders like Schizophrenia.…”

Section: Discussionsupporting

confidence: 90%

Perinatal exposure to synergistic multiple stressors leads to cellular and behavioral deficits mimicking Schizophrenia-like pathology

Sarkar

Patro

2022

Biology Open

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Protein malnourishment and immune stress are potent perinatal stressors, encountered by children born under poor socioeconomic condition. Thus, it is necessary to investigate how such stressors synergistically contribute towards developing neurological disorders in affected individuals. Pups from Wistar females, maintained on normal (high protein:HP:20%) and low protein (LP:8%) diets were used. Single and combined exposures of Poly I:C (viral mimetic:5mg/kg body wt.) and LPS (bacterial endotoxin:0.3 mg/kg body wt.) were injected to both HP and LP pups at postnatal day (PND) 3 and 9 respectively, creating 8 groups: HP (control), HP+Poly I:C, HP+LPS, HP+Poly I:C+LPS, LP, LP+Poly I:C, LP+LPS, LP+Poly I:C+LPS (multi-hit). The effects of stressors on hippocampal cytoarchitecture and behavioral abilities were studied at PND 180. LP animals were found vulnerable to immune stressors then HP animals and symptoms like neuronal damage, spine loss, downregulation of Egr 1 and Arc proteins, gliogenesis and behavioral deficits were maximum in multi-hit group. Thus, from these findings it is outlined that cellular and behavioral changes that occur following multi-hit exposure may predispose individuals to develop Schizophrenia like pathologies during adulthood.

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Section: Discussionsupporting

confidence: 90%

Perinatal exposure to synergistic multiple stressors leads to cellular and behavioral deficits mimicking Schizophrenia-like pathology

Sarkar

Patro

2022

Biology Open

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“…Decreased p-PSD-95 would mean more AMPARs would be available on the membrane to be activated. Ketamine also increased PSD-95 in the rat hippocampus ( 108 , 154 ) and normalized levels of transcription factor Egr-1 ( 154 ).…”

Section: Resultsmentioning

confidence: 96%

The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity

2022

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The mechanism of action underlying ketamine’s rapid antidepressant effects in patients with depression, both suffering from major depressive disorder (MDD) and bipolar disorder (BD), including treatment resistant depression (TRD), remains unclear. Of the many speculated routes that ketamine may act through, restoring deficits in neuroplasticity may be the most parsimonious mechanism in both human patients and preclinical models of depression. Here, we conducted a literature search using PubMed for any reports of ketamine inducing neuroplasticity relevant to depression, to identify cellular and molecular events, relevant to neuroplasticity, immediately observed with rapid mood improvements in humans or antidepressant-like effects in animals. After screening reports using our inclusion/exclusion criteria, 139 publications with data from cell cultures, animal models, and patients with BD or MDD were included (registered on PROSPERO, ID: CRD42019123346). We found accumulating evidence to support that ketamine induces an increase in molecules involved in modulating neuroplasticity, and that these changes are paired with rapid antidepressant effects. Molecules or complexes of high interest include glutamate, AMPA receptors (AMPAR), mTOR, BDNF/TrkB, VGF, eEF2K, p70S6K, GSK-3, IGF2, Erk, and microRNAs. In summary, these studies suggest a robust relationship between improvements in mood, and ketamine-induced increases in molecular neuroplasticity, particularly regarding intracellular signaling molecules.

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“…For example, exposure to chronic stress has been shown to reduce hippocampal PSD-95 protein levels (e.g. 24–26 ). Interestingly, a study in rats showed only mildly reduced levels of PSD-95 protein following forced swimming for two sessions 27 .…”

Section: Discussionmentioning

confidence: 99%

Quantitative analysis of Gria1, Gria2, Dlg1 and Dlg4 expression levels in hippocampus following forced swim stress in mice

Freudenberg

2019

Sci Rep

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AMPA receptors and interacting proteins are importantly involved in mediating stress-dependent plasticity. Previously we reported that GluA1-containing AMPA receptors and their interaction with PDZ-proteins are required for the experience-dependent expression of behavioral despair in the forced swim test. However, it is unclear if the expression of GluA1-containing AMPA receptors is affected by this type of behavior. Here we investigated in wild type mice, whether hippocampal gene or protein levels of GluA1 or associated PDZ proteins is altered following forced swim stress. We show that expression of Dlg4 (the gene coding for PSD-95) was strongly reduced after two days of forced swimming. In contrast, levels of Dlg1, Gria1, and Gria2 (coding for SAP97, GluA1, and GluA2 respectively) were not affected after one or two days of forced swimming. The changes in gene expression largely did not translate to the protein level. These findings indicate a limited acute effect of forced swim stress on the expression of the investigated targets and suggest that the acute involvement of GluA1-containing AMPA receptors tor forced swim behavior is a result of non-genomic mechanisms.

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Downregulation of Egr-1 Expression Level via GluN2B Underlies the Antidepressant Effects of Ketamine in a Chronic Unpredictable Stress Animal Model of Depression

Cited by 33 publications

References 35 publications

Perinatal exposure to synergistic multiple stressors leads to cellular and behavioral deficits mimicking Schizophrenia-like pathology

Perinatal exposure to synergistic multiple stressors leads to cellular and behavioral deficits mimicking Schizophrenia-like pathology

The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity

Quantitative analysis of Gria1, Gria2, Dlg1 and Dlg4 expression levels in hippocampus following forced swim stress in mice

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