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Targeted deletion of Vglut2 expression in the embryonal telencephalon promotes an anxiolytic phenotype of the adult mouse.

Nordenankar K, Bergfors A, Wallén-Mackenzie Å - Ups. J. Med. Sci. (2015)

Bottom Line: Anxiety is a natural emotion experienced by all individuals.Anxiolysis, the reduction of anxiety, is mediated via several large groups of therapeutical compounds, but the relief is often only temporary, and increased knowledge of the neurobiology underlying anxiety is needed in order to improve future therapies.Our results suggest that both embryonal and adolescent forebrain expression of Vglut2 normally contributes to balancing the level of anxiety.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Unit of Functional Neurobiology and Unit of Developmental Genetics, Uppsala University , Box 593, S-75214 Uppsala , Sweden.

ABSTRACT

Background: Anxiety is a natural emotion experienced by all individuals. However, when anxiety becomes excessive, it contributes to the substantial group of anxiety disorders that affect one in three people and thus are among the most common psychiatric disorders. Anxiolysis, the reduction of anxiety, is mediated via several large groups of therapeutical compounds, but the relief is often only temporary, and increased knowledge of the neurobiology underlying anxiety is needed in order to improve future therapies.

Aim: We previously demonstrated that mice lacking forebrain expression of the Vesicular glutamate transporter 2 (Vglut2) from adolescence showed a strong anxiolytic behaviour as adults. In the current study, we wished to analyse if removal of Vglut2 expression already from mid-gestation of the mouse embryo would give rise to similar anxiolysis in the adult mouse.

Methods: We produced transgenic mice lacking Vglut2 from mid-gestation and analysed their affective behaviour, including anxiety, when they had reached adulthood.

Results: The transgenic mice lacking Vglut2 expression from mid-gestation showed certain signs of anxiolytic behaviour, but this phenotype was not as prominent as when Vglut2 was removed during adolescence.

Conclusion: Our results suggest that both embryonal and adolescent forebrain expression of Vglut2 normally contributes to balancing the level of anxiety. As the neurobiological basis for anxiety is similar across species, our results in mice may help improve the current understanding of the neurocircuitry of anxiety, and hence anxiolysis, also in humans.

No MeSH data available.


Related in: MedlinePlus

No social deficits or altered despair-like behaviour, but decreased avoidance of open areas and time spent sheltered. Social behaviour analysis on adult Vglut2f/f;Emx1-Cre cKO mice and control littermates (A, B). The total time spent interacting during a 10-min social interaction session shows no alteration in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (A). The number of wins in the social dominance tube test shows that the Vglut2f/f;Emx1-Cre cKO mice do not display any altered dominance compared to control (B). The Vglut2f/f;Emx1-Cre mice spent equal time swimming during two 12 min swimming sessions separated 24 h apart in the Porsolt swim test (C). The total activity and the duration in the three different areas in the elevated plus maze show no significant differences between genotypes. The number of total entries in the outer open arm is statistically different between the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (*P < 0.05, chi-square test) (D). The total activity as measured in the multivariate concentric square field (MCSF) shows no altered behaviour for the Vglut2f/f;Emx1-Cre cKO mice compared to control mice. The frequency in the central circle and duration in the central circle as well as in central field are significantly increased for the Vglut2f/f;Emx1-Cre mice compared to control mice; the duration in the dark corner is significantly decreased in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (E). Values represent mean ± SEM. * P < 0.05 compared to control littermates. cKO = conditional knock-out.
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Figure 4: No social deficits or altered despair-like behaviour, but decreased avoidance of open areas and time spent sheltered. Social behaviour analysis on adult Vglut2f/f;Emx1-Cre cKO mice and control littermates (A, B). The total time spent interacting during a 10-min social interaction session shows no alteration in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (A). The number of wins in the social dominance tube test shows that the Vglut2f/f;Emx1-Cre cKO mice do not display any altered dominance compared to control (B). The Vglut2f/f;Emx1-Cre mice spent equal time swimming during two 12 min swimming sessions separated 24 h apart in the Porsolt swim test (C). The total activity and the duration in the three different areas in the elevated plus maze show no significant differences between genotypes. The number of total entries in the outer open arm is statistically different between the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (*P < 0.05, chi-square test) (D). The total activity as measured in the multivariate concentric square field (MCSF) shows no altered behaviour for the Vglut2f/f;Emx1-Cre cKO mice compared to control mice. The frequency in the central circle and duration in the central circle as well as in central field are significantly increased for the Vglut2f/f;Emx1-Cre mice compared to control mice; the duration in the dark corner is significantly decreased in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (E). Values represent mean ± SEM. * P < 0.05 compared to control littermates. cKO = conditional knock-out.

Mentions: Altered social skills, as measured by the social interaction test and the dominance tube test, were part of the behavioural phenotypes described for the Vglut2f/f;CaMKII-Cre cKO (13). By using the same paradigms here, no differences between the Vglut2f/f;Emx1-Cre(tg/wt) cKO and control mice were detected either in the social interaction test (P = 0.85) or in the dominance tube test (P = 0.58) (Figure 4A, B). Also, no difference between genotype groups could be discerned in the Porsolt forced swim test, a model for despair-like behaviour (trial 1, P = 0.86; trial 2 P = 0.54) (Figure 4C), which previously revealed an altered response in the Vglut2f/f;CaMKII-Cre cKO mice (13). Behavioural analysis of relevance to anxiety in humans include an apparatus which takes into advantage the rodent’s preference for familiar, dark, and/or enclosed areas (40). The EPM, which allows exploration of open versus enclosed areas is perhaps the most commonly used such method. The MCSF, which contains multiple challenges including both an open field and a dark, sheltered space, as well as challenges related to risk-assessment and risk-taking, is another valuable paradigm which we have used before (24,41,42). During a 10-minute trial, Vglut2f/f;Emx1-Cre cKO and control mice were analysed in the EPM. The number of entries (frequency) into each area; i.e. the centre, the closed, and the inner and outer segments of the open arm were scored (Figure 4D), as was the time spent (duration) in each of these compartments (Figure 4D). No differences in either total activity (the sum of all frequencies) in the maze (P = 0.84) or in any other parameter were identified (centre frequency, P = 0.83; closed arm frequency, P = 0.60; inner arm frequency, P = 0.57; outer arm frequency, P = 0.39; centre time, P = 0.20; closed arm time, P = 0.77; inner open arm time, P = 0.28; and outer open arm time; P = 0.65). However, when analysing the number of mice that entered the outer open arm, we found that significantly more cKO than control mice actually visited this exposed area (chi-square, P = 0.010) (Figure 4D). To analyse this putatively anxiolytic phenotype further, we turned to the MCSF paradigm (all statistical data are shown in Supplementary Table S3, available online). While displaying the same overall activational level as the controls (Figure 4E), the Vglut2f/f;Emx1-Cre(tg/wt) cKO mice showed a significantly decreased avoidance of the open areas as displayed by higher frequency of visits in the central circle and the time spent there (Figure 4E). The cKO mice also displayed decreased shelter-seeking in the dark room and increased time in the central field. Decreased avoidance of open areas and of the dark room were previously identified in the Vglut2f/f;CaMKII-Cre cKO mice which also showed a general hyperactivity and increased risk-assessment and exploratory behaviour. Compared to the Vglut2f/f;CaMKII-Cre cKO mice, the Vglut2f/f;Emx1-Cre cKO mice thus show a milder behavioural phenotype, but one which is more specifically centred around anxiolysis instead of strong hyperactivity in several different aspects. Taken together, the behavioural alterations identified in the EPM and the MCSF show that the Vglut2f/f;Emx1-Cre cKO mice have an anxiolytic phenotype.


Targeted deletion of Vglut2 expression in the embryonal telencephalon promotes an anxiolytic phenotype of the adult mouse.

Nordenankar K, Bergfors A, Wallén-Mackenzie Å - Ups. J. Med. Sci. (2015)

No social deficits or altered despair-like behaviour, but decreased avoidance of open areas and time spent sheltered. Social behaviour analysis on adult Vglut2f/f;Emx1-Cre cKO mice and control littermates (A, B). The total time spent interacting during a 10-min social interaction session shows no alteration in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (A). The number of wins in the social dominance tube test shows that the Vglut2f/f;Emx1-Cre cKO mice do not display any altered dominance compared to control (B). The Vglut2f/f;Emx1-Cre mice spent equal time swimming during two 12 min swimming sessions separated 24 h apart in the Porsolt swim test (C). The total activity and the duration in the three different areas in the elevated plus maze show no significant differences between genotypes. The number of total entries in the outer open arm is statistically different between the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (*P < 0.05, chi-square test) (D). The total activity as measured in the multivariate concentric square field (MCSF) shows no altered behaviour for the Vglut2f/f;Emx1-Cre cKO mice compared to control mice. The frequency in the central circle and duration in the central circle as well as in central field are significantly increased for the Vglut2f/f;Emx1-Cre mice compared to control mice; the duration in the dark corner is significantly decreased in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (E). Values represent mean ± SEM. * P < 0.05 compared to control littermates. cKO = conditional knock-out.
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Figure 4: No social deficits or altered despair-like behaviour, but decreased avoidance of open areas and time spent sheltered. Social behaviour analysis on adult Vglut2f/f;Emx1-Cre cKO mice and control littermates (A, B). The total time spent interacting during a 10-min social interaction session shows no alteration in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (A). The number of wins in the social dominance tube test shows that the Vglut2f/f;Emx1-Cre cKO mice do not display any altered dominance compared to control (B). The Vglut2f/f;Emx1-Cre mice spent equal time swimming during two 12 min swimming sessions separated 24 h apart in the Porsolt swim test (C). The total activity and the duration in the three different areas in the elevated plus maze show no significant differences between genotypes. The number of total entries in the outer open arm is statistically different between the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (*P < 0.05, chi-square test) (D). The total activity as measured in the multivariate concentric square field (MCSF) shows no altered behaviour for the Vglut2f/f;Emx1-Cre cKO mice compared to control mice. The frequency in the central circle and duration in the central circle as well as in central field are significantly increased for the Vglut2f/f;Emx1-Cre mice compared to control mice; the duration in the dark corner is significantly decreased in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (E). Values represent mean ± SEM. * P < 0.05 compared to control littermates. cKO = conditional knock-out.
Mentions: Altered social skills, as measured by the social interaction test and the dominance tube test, were part of the behavioural phenotypes described for the Vglut2f/f;CaMKII-Cre cKO (13). By using the same paradigms here, no differences between the Vglut2f/f;Emx1-Cre(tg/wt) cKO and control mice were detected either in the social interaction test (P = 0.85) or in the dominance tube test (P = 0.58) (Figure 4A, B). Also, no difference between genotype groups could be discerned in the Porsolt forced swim test, a model for despair-like behaviour (trial 1, P = 0.86; trial 2 P = 0.54) (Figure 4C), which previously revealed an altered response in the Vglut2f/f;CaMKII-Cre cKO mice (13). Behavioural analysis of relevance to anxiety in humans include an apparatus which takes into advantage the rodent’s preference for familiar, dark, and/or enclosed areas (40). The EPM, which allows exploration of open versus enclosed areas is perhaps the most commonly used such method. The MCSF, which contains multiple challenges including both an open field and a dark, sheltered space, as well as challenges related to risk-assessment and risk-taking, is another valuable paradigm which we have used before (24,41,42). During a 10-minute trial, Vglut2f/f;Emx1-Cre cKO and control mice were analysed in the EPM. The number of entries (frequency) into each area; i.e. the centre, the closed, and the inner and outer segments of the open arm were scored (Figure 4D), as was the time spent (duration) in each of these compartments (Figure 4D). No differences in either total activity (the sum of all frequencies) in the maze (P = 0.84) or in any other parameter were identified (centre frequency, P = 0.83; closed arm frequency, P = 0.60; inner arm frequency, P = 0.57; outer arm frequency, P = 0.39; centre time, P = 0.20; closed arm time, P = 0.77; inner open arm time, P = 0.28; and outer open arm time; P = 0.65). However, when analysing the number of mice that entered the outer open arm, we found that significantly more cKO than control mice actually visited this exposed area (chi-square, P = 0.010) (Figure 4D). To analyse this putatively anxiolytic phenotype further, we turned to the MCSF paradigm (all statistical data are shown in Supplementary Table S3, available online). While displaying the same overall activational level as the controls (Figure 4E), the Vglut2f/f;Emx1-Cre(tg/wt) cKO mice showed a significantly decreased avoidance of the open areas as displayed by higher frequency of visits in the central circle and the time spent there (Figure 4E). The cKO mice also displayed decreased shelter-seeking in the dark room and increased time in the central field. Decreased avoidance of open areas and of the dark room were previously identified in the Vglut2f/f;CaMKII-Cre cKO mice which also showed a general hyperactivity and increased risk-assessment and exploratory behaviour. Compared to the Vglut2f/f;CaMKII-Cre cKO mice, the Vglut2f/f;Emx1-Cre cKO mice thus show a milder behavioural phenotype, but one which is more specifically centred around anxiolysis instead of strong hyperactivity in several different aspects. Taken together, the behavioural alterations identified in the EPM and the MCSF show that the Vglut2f/f;Emx1-Cre cKO mice have an anxiolytic phenotype.

Bottom Line: Anxiety is a natural emotion experienced by all individuals.Anxiolysis, the reduction of anxiety, is mediated via several large groups of therapeutical compounds, but the relief is often only temporary, and increased knowledge of the neurobiology underlying anxiety is needed in order to improve future therapies.Our results suggest that both embryonal and adolescent forebrain expression of Vglut2 normally contributes to balancing the level of anxiety.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Unit of Functional Neurobiology and Unit of Developmental Genetics, Uppsala University , Box 593, S-75214 Uppsala , Sweden.

ABSTRACT

Background: Anxiety is a natural emotion experienced by all individuals. However, when anxiety becomes excessive, it contributes to the substantial group of anxiety disorders that affect one in three people and thus are among the most common psychiatric disorders. Anxiolysis, the reduction of anxiety, is mediated via several large groups of therapeutical compounds, but the relief is often only temporary, and increased knowledge of the neurobiology underlying anxiety is needed in order to improve future therapies.

Aim: We previously demonstrated that mice lacking forebrain expression of the Vesicular glutamate transporter 2 (Vglut2) from adolescence showed a strong anxiolytic behaviour as adults. In the current study, we wished to analyse if removal of Vglut2 expression already from mid-gestation of the mouse embryo would give rise to similar anxiolysis in the adult mouse.

Methods: We produced transgenic mice lacking Vglut2 from mid-gestation and analysed their affective behaviour, including anxiety, when they had reached adulthood.

Results: The transgenic mice lacking Vglut2 expression from mid-gestation showed certain signs of anxiolytic behaviour, but this phenotype was not as prominent as when Vglut2 was removed during adolescence.

Conclusion: Our results suggest that both embryonal and adolescent forebrain expression of Vglut2 normally contributes to balancing the level of anxiety. As the neurobiological basis for anxiety is similar across species, our results in mice may help improve the current understanding of the neurocircuitry of anxiety, and hence anxiolysis, also in humans.

No MeSH data available.


Related in: MedlinePlus