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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

The Vglut2f/f;Emx1-Cre mice do not show any altered response to amphetamine. The initial response to novel environment (30 min) and overall response after i.p. injection of saline (90 min), 10 mg/kg, in locomotion, periferal activity, and corner activity are unaltered in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (B, D, F). On day 2, the mice were subjected to the activity boxes for 30 min and were thereafter administered 1.5 mg/kg amphetamine i.p. and were recorded for 90 min (A, C, E). The arrows in the graphs depict the time of saline and amphetamine injection. Data were analysed with two-way ANOVA and showed no significant interactions (effect of genotype). Data are represented as mean ± SEM. cKO = conditional knock-out.
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Figure 3: The Vglut2f/f;Emx1-Cre mice do not show any altered response to amphetamine. The initial response to novel environment (30 min) and overall response after i.p. injection of saline (90 min), 10 mg/kg, in locomotion, periferal activity, and corner activity are unaltered in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (B, D, F). On day 2, the mice were subjected to the activity boxes for 30 min and were thereafter administered 1.5 mg/kg amphetamine i.p. and were recorded for 90 min (A, C, E). The arrows in the graphs depict the time of saline and amphetamine injection. Data were analysed with two-way ANOVA and showed no significant interactions (effect of genotype). Data are represented as mean ± SEM. cKO = conditional knock-out.

Mentions: The behavioural analyses of the previously reported Vglut2f/f;CaMKII-Cre cKO mice revealed a spontaneous hyperactivity which was further accentuated above the levels of the controls when mice were challenged with an acute dose of amphetamine (13). This increased behavioural activation was correlated with increased basal levels of dopamine in the striatum, which we suggested as the underlying cause of the hyperactivity (13), in accordance with the role of dopamine in general activational response (39). Caretaker handling of the Vglut2f/f;Emx1-Cre(tg/wt) cKO mice now revealed that these mice were calmer than the Vglut2f/f;CaMKII-Cre cKO mice, which we previously had experienced as difficult to handle due to the strong hyperactivity. This observation tentatively suggested that the telencephalic deletion of Vglut2 from embryo development (Vglut2f/f;Emx1-Cre cKO) had a different effect on behaviour than had the postnatal deletion (Vglut2f/f;CaMKII-Cre cKO). By comparing spontaneous and amphetamine-induced activity between the Vglut2f/f;Emx1-Cre cKO mice and their littermate control mice, no statistically relevant difference in either locomotion, corner activity, or peripheral activity was detected between genotypes either pre- or post-injection by saline or amphetamine (Figure 3A–F) (all statistical data are shown in Supplementary Table S2, available online). Further, we did not find any weight differences between either male (ctrl n = 11, 30.4 ± 0.7 g; cKO n = 6, 28.7 ± 0.4 g, P = 0.13) or female mice (n = 10, 22.1 ± 0.8 g; cKO n = 8, 22.5 ± 0.9 g, P = 0.75) of the different genotype groups, indicating normal food intake and activational levels in the cKO mice. Biochemical detection of DA and its metabolite DOPAC as well as noradrenalin, 3-MT, and 5-HT in tissue dissected from the dorsal (caudate putamen) and ventral (nucleus accumbens) striatum did not reveal any differences between the Vglut2f/f;Emx1-Cre(tg/wt) cKO and control mice (Table II). Taken together, these results show that adult mice lacking Vglut2 in selected telencephalic areas from early developmental stages show normal spontaneous and amphetamine-induced activity as well as normal levels of monoamines DA, NA, 5-HT, and their metabolites in the striatum.


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)

The Vglut2f/f;Emx1-Cre mice do not show any altered response to amphetamine. The initial response to novel environment (30 min) and overall response after i.p. injection of saline (90 min), 10 mg/kg, in locomotion, periferal activity, and corner activity are unaltered in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (B, D, F). On day 2, the mice were subjected to the activity boxes for 30 min and were thereafter administered 1.5 mg/kg amphetamine i.p. and were recorded for 90 min (A, C, E). The arrows in the graphs depict the time of saline and amphetamine injection. Data were analysed with two-way ANOVA and showed no significant interactions (effect of genotype). Data are represented as mean ± SEM. cKO = conditional knock-out.
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Figure 3: The Vglut2f/f;Emx1-Cre mice do not show any altered response to amphetamine. The initial response to novel environment (30 min) and overall response after i.p. injection of saline (90 min), 10 mg/kg, in locomotion, periferal activity, and corner activity are unaltered in the Vglut2f/f;Emx1-Cre cKO mice compared to control mice (B, D, F). On day 2, the mice were subjected to the activity boxes for 30 min and were thereafter administered 1.5 mg/kg amphetamine i.p. and were recorded for 90 min (A, C, E). The arrows in the graphs depict the time of saline and amphetamine injection. Data were analysed with two-way ANOVA and showed no significant interactions (effect of genotype). Data are represented as mean ± SEM. cKO = conditional knock-out.
Mentions: The behavioural analyses of the previously reported Vglut2f/f;CaMKII-Cre cKO mice revealed a spontaneous hyperactivity which was further accentuated above the levels of the controls when mice were challenged with an acute dose of amphetamine (13). This increased behavioural activation was correlated with increased basal levels of dopamine in the striatum, which we suggested as the underlying cause of the hyperactivity (13), in accordance with the role of dopamine in general activational response (39). Caretaker handling of the Vglut2f/f;Emx1-Cre(tg/wt) cKO mice now revealed that these mice were calmer than the Vglut2f/f;CaMKII-Cre cKO mice, which we previously had experienced as difficult to handle due to the strong hyperactivity. This observation tentatively suggested that the telencephalic deletion of Vglut2 from embryo development (Vglut2f/f;Emx1-Cre cKO) had a different effect on behaviour than had the postnatal deletion (Vglut2f/f;CaMKII-Cre cKO). By comparing spontaneous and amphetamine-induced activity between the Vglut2f/f;Emx1-Cre cKO mice and their littermate control mice, no statistically relevant difference in either locomotion, corner activity, or peripheral activity was detected between genotypes either pre- or post-injection by saline or amphetamine (Figure 3A–F) (all statistical data are shown in Supplementary Table S2, available online). Further, we did not find any weight differences between either male (ctrl n = 11, 30.4 ± 0.7 g; cKO n = 6, 28.7 ± 0.4 g, P = 0.13) or female mice (n = 10, 22.1 ± 0.8 g; cKO n = 8, 22.5 ± 0.9 g, P = 0.75) of the different genotype groups, indicating normal food intake and activational levels in the cKO mice. Biochemical detection of DA and its metabolite DOPAC as well as noradrenalin, 3-MT, and 5-HT in tissue dissected from the dorsal (caudate putamen) and ventral (nucleus accumbens) striatum did not reveal any differences between the Vglut2f/f;Emx1-Cre(tg/wt) cKO and control mice (Table II). Taken together, these results show that adult mice lacking Vglut2 in selected telencephalic areas from early developmental stages show normal spontaneous and amphetamine-induced activity as well as normal levels of monoamines DA, NA, 5-HT, and their metabolites in the striatum.

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