Behavioral analysis in mice deficient for GAREM2 (Grb2-associated regulator of Erk/MAPK subtype2) that is a subtype of highly expressing in the brain

Nishino, Tasuku; Tamada, Kota; Maeda, Akane; Abe, Takaya; Kanazawa, Hiroshi; Funahashi, Yasuhiro; Kaibuchi, Kozo; Takumi, Toru; Konishi, Hiroaki

doi:10.1186/s13041-019-0512-x

Cited by 11 publications

(9 citation statements)

References 54 publications

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“…Additionally, it is interesting to explore whether corticosterone levels reflect “anxiety” levels that are naturally induced by exposure to potentially aversive situations in the elevated plus maze in C57BL/6J mice. In the present study, to examine the influences of experience with a battery of behavioral tests that did not include the elevated plus maze test on subsequent elevated plus maze behavior and plasma corticosterone responses in male C57BL/6J mice, animals were first subjected to a behavioral test battery, including an assessment of general health and neurological reflexes, a light/dark transition test, and an open field test, which have been extensively used to characterize the behavioral phenotypes of many strains of mutant and inbred mice in our laboratory [e.g., 40 – 43 ] and in other laboratories [e.g., 44 – 47 ]. Mice with and without experience with the behavioral test battery were tested in the elevated plus maze, and immediately after exposure to the maze, their blood was collected to measure plasma corticosterone levels.…”

Section: Introductionmentioning

confidence: 99%

Effects of test experience, closed-arm wall color, and illumination level on behavior and plasma corticosterone response in an elevated plus maze in male C57BL/6J mice: a challenge against conventional interpretation of the test

Shoji

Miyakawa

2021

Mol Brain

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The elevated plus maze test is a widely used test for assessing anxiety-like behavior and screening novel therapeutic agents in rodents. Previous studies have shown that a variety of internal factors and procedural variables can influence elevated plus maze behavior. Although some studies have suggested a link between behavior and plasma corticosterone levels, the relationships between them remain unclear. In this study, we investigated the effects of experience with a battery of behavioral tests, the wall color of the closed arms, and illumination level on the behavior and plasma corticosterone responses in the elevated plus maze in male C57BL/6J mice. Mice were either subjected to a series of behavioral tests, including assessments of general health and neurological function, a light/dark transition test, and an open field test, or left undisturbed until the start of the elevated plus maze test. The mice with and without test battery experience were allowed to freely explore the elevated plus maze. The other two independent groups of naïve mice were tested in mazes with closed arms with different wall colors (clear, transparent blue, white, and black) or different illumination levels (5, 100, and 800 lx). Immediately after the test, blood was collected to measure plasma corticosterone concentrations. Mice with test battery experience showed a lower percentage of open arm time and entries and, somewhat paradoxically, had lower plasma corticosterone levels than the mice with no test battery experience. Mice tested in the maze with closed arms with clear walls exhibited higher open arm exploration than mice tested in the maze with closed arms with black walls, while there were no significant differences in plasma corticosterone levels between the different wall color conditions. Illumination levels had no significant effects on any measure. Our results indicate that experience with other behavioral tests and different physical features of the maze affect elevated plus maze behaviors. Increased open arm time and entries are conventionally interpreted as decreased anxiety-like behavior, while other possible interpretations are considered: open arm exploration may reflect heightened anxiety and panic-like reaction to a novel situation under certain conditions. With the possibility of different interpretations, the present findings highlight the need to carefully consider the test conditions in designing experiments and drawing conclusions from the behavioral outcomes in the elevated plus maze test in C57BL/6J mice.

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Section: Introductionmentioning

confidence: 99%

Effects of test experience, closed-arm wall color, and illumination level on behavior and plasma corticosterone response in an elevated plus maze in male C57BL/6J mice: a challenge against conventional interpretation of the test

Shoji

Miyakawa

2021

Mol Brain

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“…According to the results of a comprehensive behavioral battery, there were slight emotional differences between GAREM2 knockout and wild-type mice, and the knockout mice exhibited less anxiety, mildly increased social approach behavior, and longer latency to immobility. Additionally, neurite extension was suppressed in the primary culture of neurons derived from GAREM2 KO mice [10]. Studies using knockout animals have not revealed a relationship between GAREM2 function and neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of GAREM2 knockout mice showed that while the loss of GAREM2 does not cause significant changes in brain function itself, these knockout mice exhibited emotional alterations, such as less anxiety, mildly increased social approaching behavior, and longer latency to immobility as compared to wild-type mice (WT) [10]. Furthermore, neurite outgrowth in primary cultured neurons was suppressed in neurons derived from GAREM2 knockout mice.…”

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confidence: 99%

Effect of the glycine-rich domain in GAREM2 on its unique subcellular localization upon EGF stimulation

et al. 2021

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Background In mammals, there are two subtypes of Grb2-associated regulator of Erk/MAPK (GAREM), an adaptor protein that functions downstream of the cell growth factor receptor. GAREM1 is ubiquitously expressed, whereas GAREM2 is mainly expressed in the brain. However, the precise mechanism of the translocation of each GAREM subtype in growth factor-stimulated cells is still unclear. Methods In this study, immunofluorescence staining with specific antibodies against each GAREM subtype and time-lapse analysis using GFP fusion proteins were used to analyze the subcellular localization of each GAREM subtype in a cell growth stimulus-dependent manner. We also biochemically analyzed the correlation between its subcellular localization and tyrosine phosphorylation of GAREM2. Results We found that endogenously and exogenously expressed GAREM2 specifically aggregated and formed granules in NGF-stimulated PC-12 cells and in EGF-stimulated COS-7 cells. Based on the observed subcellular localizations of chimeric GAREM1 and GAREM2 proteins, a glycine-rich region, which is present only in GAREM2, is required for the observed granule formation. This region also regulates the degree of EGF-stimulation-dependent tyrosine phosphorylation of GAREM2. Conclusions Our results, showing that aggregation of GAREM2 in response to EGF stimulation is dependent on a glycine-rich region, suggest that GAREM2 aggregation may be involved in neurodegenerative diseases.

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“…The test was conducted for 10 min. 29 The immobility time, which is indicative of helpless behavior, was recorded. 30 …”

Section: Methodsmentioning

confidence: 99%

“…The test was conducted for 10 min. 29 The immobility time, which is indicative of helpless behavior, was recorded. 30 In the forced swim test (FST), the mice swam in an open glass beaker (height 18.5 cm and diameter 14.5 cm) filled with water (23-25 °C) up to a height of 12 cm to prevent the mice from supporting themselves against the bottom of the beaker.…”

Section: Behavioral Testsmentioning

confidence: 99%

SIRT1/FOXO1 Axis-Mediated Hippocampal Angiogenesis is Involved in the Antidepressant Effect of Chaihu Shugan San

Zhang¹,

Lu²,

Shi³

et al. 2022

DDDT

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Objective: Chaihu Shugan San (CSS) has a long history for treating major depressive disorder (MDD), which has been verified effectively and safely in clinical studies. Deficient angiogenesis plays important roles in MDD. However, the underlying mechanisms of CSS on angiogenesis remain poorly understood. Methods: Network pharmacology analysis was applied to explore the potential angiogenic targets and pathways between CSS and MDD. These targets would be validated in chronic unpredictable mild stress (CUMS)-induced depressive-like mice by Western blots, immunofluorescence, and immunohistochemistry. Then, the underlying molecular mechanisms were further investigated in brain microvascular endothelial cells (BMVECs) with CSS-containing serum by Western blots and immunofluorescence. Results: Network pharmacology analysis showed that the antidepressant role of CSS was closely associated with Silent information regulator protein 1 (SIRT1)/Forkhead box O1 (FOXO1) axis-mediated angiogenesis. This prediction was confirmed in the following experiments. CSS induced angiogenesis, increased SIRT1 expression, and decreased FOXO1 expression in the hippocampus of CUMS mice. Five percent CSS-containing serum produced a significant increase in BMVECs proliferation, migration, and tube formation, but these effects were reduced by SIRT1 silencing. CSS serum could also promote FOXO1 translocation to the cytoplasm through SIRT1 signaling, which triggered FOXO1 protein degradation. What is more, CSS upregulated VEGFA and BDNF expressions not only in the hippocampus of depressive mice but also in BMVECs supernatants. Of note, these trophic factors play important roles in promoting neurogenesis. Conclusion:The study showed that CSS could promote angiogenesis and neurogenesis in the hippocampus of CUMS-induced mice. The underlying molecular mechanism involves the SIRT1/FOXO1 axis and subsequent regulation of VEGFA and BDNF. These findings provide novel insight into CSS drug development, and targeting the SIRT1/FOXO1 axis might be a promising strategy to treat MDD.

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Behavioral analysis in mice deficient for GAREM2 (Grb2-associated regulator of Erk/MAPK subtype2) that is a subtype of highly expressing in the brain

Cited by 11 publications

References 54 publications

Effects of test experience, closed-arm wall color, and illumination level on behavior and plasma corticosterone response in an elevated plus maze in male C57BL/6J mice: a challenge against conventional interpretation of the test

Effects of test experience, closed-arm wall color, and illumination level on behavior and plasma corticosterone response in an elevated plus maze in male C57BL/6J mice: a challenge against conventional interpretation of the test

Effect of the glycine-rich domain in GAREM2 on its unique subcellular localization upon EGF stimulation

SIRT1/FOXO1 Axis-Mediated Hippocampal Angiogenesis is Involved in the Antidepressant Effect of Chaihu Shugan San

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