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Selective deletion of forebrain glycogen synthase kinase 3β reveals a central role in serotonin-sensitive anxiety and social behaviour.

Latapy C, Rioux V, Guitton MJ, Beaulieu JM - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2012)

Bottom Line: Behavioural characterization showed that suppression of GSK3β in these brain areas has anxiolytic and pro-social effects.However, while a global reduction of GSK2β expression reduced responsiveness to amphetamine and increased resilience to social defeat, these behavioural effects were not found in CamKIIcre-floxGSK3β mice.These findings demonstrate a dissociation of behavioural effects related to GSK3 inhibition, with forebrain GSK3β being involved in the regulation of anxiety and sociability while social preference, resilience and responsiveness to psychostimulants would involve a function of this kinase in subcortical areas such as the hippocampus and striatum.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neuroscience, Laval University, , Quebec City, Quebec, Canada.

ABSTRACT
Serotonin (5-HT) neurotransmission is thought to underlie mental illnesses, such as bipolar disorder, depression, autism and schizophrenia. Independent studies have indicated that 5-HT or drugs acting on 5-HT neurotransmission regulate the serine/threonine kinase glycogen synthase kinase 3β (GSK3β). Furthermore, GSK3β inhibition rescues behavioural abnormalities in 5-HT-deficient mice with a loss-of-function mutation equivalent to the human variant (R441H) of tryptophan hydroxylase 2. In an effort to define neuroanatomical correlates of GSK3β activity in the regulation of behaviour, we generated CamKIIcre-floxGSK3β mice in which the gsk3b gene is postnatally inactivated in forebrain pyramidal neurons. Behavioural characterization showed that suppression of GSK3β in these brain areas has anxiolytic and pro-social effects. However, while a global reduction of GSK2β expression reduced responsiveness to amphetamine and increased resilience to social defeat, these behavioural effects were not found in CamKIIcre-floxGSK3β mice. These findings demonstrate a dissociation of behavioural effects related to GSK3 inhibition, with forebrain GSK3β being involved in the regulation of anxiety and sociability while social preference, resilience and responsiveness to psychostimulants would involve a function of this kinase in subcortical areas such as the hippocampus and striatum.

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Response to acute amphetamine treatment. (a) Time course of locomotor-induced behaviour in response to an i.p. injection of 2 mg kg–1 amphetamine or saline solution in NEG (filled circles, vehicle (n = 8); filled triangles, amphetamine 2 mg kg–1 (n = 8)) and POS (unfilled circles, vehicle (n = 8); unfilled triangles, amphetamine 2 mg kg–1 (n = 7)) mice, expressed in distance travelled per 5 min blocks. (b) Cumulated distance travelled during the first 90 min after amphetamine treatment in NEG (n = 8) and POS (n = 7) mice. (c) Time course response to amphetamine of NEG (filled bars, n = 8) and POS (unfilled bars, n = 7) mice expressed in distance travelled per 30 min blocks. Data are presented as means ± s.e.m.; *p ≤ 0.05. Two-tailed Student's t-test was used.
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RSTB20120094F4: Response to acute amphetamine treatment. (a) Time course of locomotor-induced behaviour in response to an i.p. injection of 2 mg kg–1 amphetamine or saline solution in NEG (filled circles, vehicle (n = 8); filled triangles, amphetamine 2 mg kg–1 (n = 8)) and POS (unfilled circles, vehicle (n = 8); unfilled triangles, amphetamine 2 mg kg–1 (n = 7)) mice, expressed in distance travelled per 5 min blocks. (b) Cumulated distance travelled during the first 90 min after amphetamine treatment in NEG (n = 8) and POS (n = 7) mice. (c) Time course response to amphetamine of NEG (filled bars, n = 8) and POS (unfilled bars, n = 7) mice expressed in distance travelled per 30 min blocks. Data are presented as means ± s.e.m.; *p ≤ 0.05. Two-tailed Student's t-test was used.

Mentions: To further explore the role of GSK3β in the behavioural effects of amphetamine, an effective dose (2 mg kg–1 of body weight i.p.) was administered to POS and NEG animals. Amphetamine induced hyperlocomotion in NEG animals as well in POS mice (figure 4a). Quantification of locomotor activity for a period of 90 min following drug administration revealed an overall stronger responsiveness to amphetamine in mice with forebrain GSK3β deficiency (figure 4b). A time-course analysis of the whole duration of the test showed that, whereas POS and NEG mice have similar responses to amphetamine initially, POS mice were significantly more responsive to amphetamine, between 30 and 90 min after drug administration (figure 4c). These observations are in stark contrast to the overall reduction in locomotor responsiveness to amphetamine reported in systemic GSK3β HET mice [32], and suggests that GSK3β expressed in different brain regions may play differential roles in modulating responsiveness to this drug.Figure 4.


Selective deletion of forebrain glycogen synthase kinase 3β reveals a central role in serotonin-sensitive anxiety and social behaviour.

Latapy C, Rioux V, Guitton MJ, Beaulieu JM - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2012)

Response to acute amphetamine treatment. (a) Time course of locomotor-induced behaviour in response to an i.p. injection of 2 mg kg–1 amphetamine or saline solution in NEG (filled circles, vehicle (n = 8); filled triangles, amphetamine 2 mg kg–1 (n = 8)) and POS (unfilled circles, vehicle (n = 8); unfilled triangles, amphetamine 2 mg kg–1 (n = 7)) mice, expressed in distance travelled per 5 min blocks. (b) Cumulated distance travelled during the first 90 min after amphetamine treatment in NEG (n = 8) and POS (n = 7) mice. (c) Time course response to amphetamine of NEG (filled bars, n = 8) and POS (unfilled bars, n = 7) mice expressed in distance travelled per 30 min blocks. Data are presented as means ± s.e.m.; *p ≤ 0.05. Two-tailed Student's t-test was used.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3405679&req=5

RSTB20120094F4: Response to acute amphetamine treatment. (a) Time course of locomotor-induced behaviour in response to an i.p. injection of 2 mg kg–1 amphetamine or saline solution in NEG (filled circles, vehicle (n = 8); filled triangles, amphetamine 2 mg kg–1 (n = 8)) and POS (unfilled circles, vehicle (n = 8); unfilled triangles, amphetamine 2 mg kg–1 (n = 7)) mice, expressed in distance travelled per 5 min blocks. (b) Cumulated distance travelled during the first 90 min after amphetamine treatment in NEG (n = 8) and POS (n = 7) mice. (c) Time course response to amphetamine of NEG (filled bars, n = 8) and POS (unfilled bars, n = 7) mice expressed in distance travelled per 30 min blocks. Data are presented as means ± s.e.m.; *p ≤ 0.05. Two-tailed Student's t-test was used.
Mentions: To further explore the role of GSK3β in the behavioural effects of amphetamine, an effective dose (2 mg kg–1 of body weight i.p.) was administered to POS and NEG animals. Amphetamine induced hyperlocomotion in NEG animals as well in POS mice (figure 4a). Quantification of locomotor activity for a period of 90 min following drug administration revealed an overall stronger responsiveness to amphetamine in mice with forebrain GSK3β deficiency (figure 4b). A time-course analysis of the whole duration of the test showed that, whereas POS and NEG mice have similar responses to amphetamine initially, POS mice were significantly more responsive to amphetamine, between 30 and 90 min after drug administration (figure 4c). These observations are in stark contrast to the overall reduction in locomotor responsiveness to amphetamine reported in systemic GSK3β HET mice [32], and suggests that GSK3β expressed in different brain regions may play differential roles in modulating responsiveness to this drug.Figure 4.

Bottom Line: Behavioural characterization showed that suppression of GSK3β in these brain areas has anxiolytic and pro-social effects.However, while a global reduction of GSK2β expression reduced responsiveness to amphetamine and increased resilience to social defeat, these behavioural effects were not found in CamKIIcre-floxGSK3β mice.These findings demonstrate a dissociation of behavioural effects related to GSK3 inhibition, with forebrain GSK3β being involved in the regulation of anxiety and sociability while social preference, resilience and responsiveness to psychostimulants would involve a function of this kinase in subcortical areas such as the hippocampus and striatum.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neuroscience, Laval University, , Quebec City, Quebec, Canada.

ABSTRACT
Serotonin (5-HT) neurotransmission is thought to underlie mental illnesses, such as bipolar disorder, depression, autism and schizophrenia. Independent studies have indicated that 5-HT or drugs acting on 5-HT neurotransmission regulate the serine/threonine kinase glycogen synthase kinase 3β (GSK3β). Furthermore, GSK3β inhibition rescues behavioural abnormalities in 5-HT-deficient mice with a loss-of-function mutation equivalent to the human variant (R441H) of tryptophan hydroxylase 2. In an effort to define neuroanatomical correlates of GSK3β activity in the regulation of behaviour, we generated CamKIIcre-floxGSK3β mice in which the gsk3b gene is postnatally inactivated in forebrain pyramidal neurons. Behavioural characterization showed that suppression of GSK3β in these brain areas has anxiolytic and pro-social effects. However, while a global reduction of GSK2β expression reduced responsiveness to amphetamine and increased resilience to social defeat, these behavioural effects were not found in CamKIIcre-floxGSK3β mice. These findings demonstrate a dissociation of behavioural effects related to GSK3 inhibition, with forebrain GSK3β being involved in the regulation of anxiety and sociability while social preference, resilience and responsiveness to psychostimulants would involve a function of this kinase in subcortical areas such as the hippocampus and striatum.

Show MeSH
Related in: MedlinePlus