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Hyperactivity: Glycogen synthase kinase-3 as a therapeutic target
European Journal of Pharmacology 708 (2013) 56–59
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Perspective
Hyperactivity: Glycogen synthase kinase-3 as a therapeutic target Marjelo A. Mines n Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 14 December 2012 Received in revised form 15 February 2013 Accepted 24 February 2013 Available online 14 March 2013
The diagnosis of hyperactivity-associated disorders has increased within the past few years. The prevalence of hyperactivity-associated disorders is indicative of the need to more fully understand the underlying causes and to develop improved therapeutic interventions. There is increasing evidence that glycogen synthase kinase-3 (GSK3) mediates locomotor hyperactivity in a number of animal models, and therefore may be a potential target for therapeutic intervention in hyperactivity-associated behaviors. In this review, we discuss 1) the effect of manipulations of GSK3 in the absence of drugs and disorders on locomotor activity, 2) the role of GSK3 in drug-induced hyperactivity in rodents, and 3) regulation of locomotor activity by GSK3 in transgenic mouse models related to specific disorders. These studies link GSK3 regulation and activity to hyperactivity-associated behaviors and disease pathologies. & 2013 Elsevier B.V. All rights reserved.
Keywords: Amphetamine Attention-deficit/hyperactivity disorder Glycogen synthase-kinase 3 Locomotor hyperactivity Stimulants
1. Introduction Within the last five years, the diagnosis of disorders involving a hyperactivity component, such as bipolar disorder and attention deficit/hyperactivity disorder (ADHD), has become increasingly common, particularly in young people. The prevalence of hyperactivityassociated disorders is indicative of the need to more fully understand the underlying causes and to develop improved therapeutic interventions. Current therapies for hyperactivity disorders include stimulantbased medications, antidepressants, mood stabilizers, and psychotherapy (behavior modification therapy) (Center for Disease Control, 2010). Recently there is increasing evidence that inadequately controlled glycogen synthase kinase-3 (GSK3) underlies hyperactivity in a number of animal models, and thus may be a potential target for therapeutic intervention in hyperactivityassociated behaviors. GSK3 is a serine/threonine kinase first identified as an enzyme involved in glycogen synthesis, specifically by phosphorylating glycogen synthase. GSK3 has since been found to regulate over 50 substrates (Jope and Johnson, 2004). Accordingly, GSK3 regulates many fundamental processes, including development, cell structure, microtubule dynamics, gene expression, and cell survival (Frame and Cohen, 2001; Grimes and Jope, 2001). GSK3 exists as two isoforms, GSK3α and GSK3β (Woodgett, 1990), which often, but not exclusively, share functions (McManus et al., 2005; Polter and Li, 2011; Lal et al., 2012). GSK3 is constitutively partially active in cells. Therefore, input signals
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regulate GSK3 by decreasing or increasing its activity. The most prevalent mechanism regulating the activity of GSK3 is inhibition by phosphorylation on serine-21 of GSK3α and serine-9 of GSK3β. Several kinases mediate this serine-phosphorylation, which inhibits GSK3 activity (Jope and Johnson, 2004). Studies in rodents have linked GSK3 abnormalities to a surprisingly large and diverse number of conditions involving locomotor hyperactivity, in part by using GSK3 inhibitors such as lithium (Klein and Melton, 1996). Here, we review the information linking GSK3 to hyperactivityassociated behaviors and its involvement in disease pathologies.
2. Manipulations of GSK3 in the absence of drugs or disorders The most direct means to test the role of GSK3 in locomotor activity is to examine this relationship in mice with increased or decreased GSK3 levels or activity. Studies in healthy wild-type mice given GSK3 inhibitors most often report unaltered locomotor activity (Yuskaitis et al., 2010; O’Brien et al., 2011). Several rodent models containing genetic manipulations of GSK3 have been used to test GSK3 involvement in hyperactivity. Prickaerts et al. (2006) reported increased locomotor activity in mice expressing neuron-specific constitutively active GSK3, generated by serine-to-alanine mutations in the regulatory serines of both GSK3 isoforms, thereby inhibiting serine-mediated phosphorylation and preventing inhibition of GSK3. Mice lacking a functional GSK3α gene, resulting in the absence of GSK3α, displayed reduced open-field locomotor activity and reduced aggression (Kaidanovich-Beilin et al., 2009). GSK3 gene polymorphisms have been reported to be associated with the risk and pathology of ADHD. Shim et al. (2012) reported
M.A. Mines / European Journal of Pharmacology 708 (2013) 56–59
that incidence of the −1727 A/T single nucleotide polymorphism (SNP) of GSK3β gene was increased in ADHD patients. This finding bolstered a link between GSK3 and hyperactivity, specifically in ADHD, but warrants further study to identify the mechanism.
3. Drug-induced hyperactivity The most well-established link between activation of GSK3 and locomotor activity in rodents is in the dopamine 2 (D2) receptormediated responses to stimulants, such as amphetamine. Altered dopaminergic activity has been linked to neurological diseases, such as ADHD, schizophrenia, and Parkinson's disease (Carlsson, 2001; Gainetdinov and Caron, 2003). Psychostimulants, such as methylphenidate and amphetamine, are commonly used therapeutic options for ADHD and reduce associated symptoms (Cantwell, 1996; Solanto, 2002; Olfson et al., 2003). These drugs target the dopaminergic system via regulation of intracellular signaling mediated by the D1 and D2 families of dopamine receptors. In wild-type mice, inhibition of GSK3 decreased amphetamineinduced hyperactivity (Mines et al. 2013, Beaulieu et al., 2004, 2005, 2007). Administration of lithium, and other GSK3 inhibitors, attenuated amphetamine-induced hyperactivity behaviors in mice (Beaulieu et al., 2004, Kozikowski et al., 2007; Kalinichev and Dawson, 2011; Enman and Unterwald, 2012). Recently, research has established a link between dopamine receptors and signal mechanisms involving GSK3 (Beaulieu et al., 2009; DeFea, 2011; Shenoy and Lefkowitz, 2011). Acute treatment with stimulants causes a rapid increase in locomotor activity in rodents. The locomotion-inducing effect of amphetamine is mediated by activation of GSK3 (Beaulieu et al., 2004; Beaulieu et al., 2007). Akt, also known as Protein Kinase B (PKB), inhibits GSK3 activity through increases in inhibitory serine-phosphorylation of serine21-GSK3α and serine-9-GSK3β (Doble and Woodgett, 2003; Jope and Johnson, 2004). Both acute and long term amphetamine and methylphenidate administration decreased inhibitory serinephosphorylation of GSKα and GSK3β in the striatum by decreasing the activating phosphorylation of Akt on threonine-308-Akt (Mines and Jope, 2012; Beaulieu et al., 2004; Beaulieu et al., 2007). Stimulation of D2 receptors modulates the regulatory phosphorylation of GSK3 and Akt by altering the β-arrestin-2/ Akt/protein phosphatase 2, catalytic subunit α (PP2Ac)/GSK3 complex (Beaulieu et al., 2008). D2-mediated activity promotes the association of β-arrestin with active GSK3 (unphosphorylated) and active Akt (phosphorylated) (Fig. 1A). PP2Ac is recruited to dephosphorylate Akt, thereby inactivating Akt and preventing Aktmediated inhibition (phosphorylation) of GSK. Beaulieu et al. (2004, 2008, 2011) showed that regulation of this complex is required for amphetamine-induced locomotor hyperactivity. O’Brien et al. (2011) also examined the association of GSK3, β-arrestin, and Akt. In striatal homogenates from wild-type mice, GSK3 inhibitors promoted decreased association of Akt with PP2Ac and β-arrestin (Fig. 1B), suggesting that active GSK3 is required for complex formation. Conversely, increased Akt-PP2Ac association was found in GSK3 over-expressing mice, PrpGsk3β mice. While lithium treatment significantly decreased the association of Akt and PP2Ac in wild-type mice, it had no effect on Akt-PP2Ac association in PrpGsk3β mice, suggesting the need for GSK3 for complex stabilization (O’Brien et al., 2011). The association of Akt and PP2Ac in Gsk3β þ /− mice was identical to wild-type mice treated with lithium, showing decreased association. Cumulatively, these reports establish GSK3 as a key contributor to the formation, stability, and activity of this complex. Mice expressing constitutive activation of GSK3 are hypersensitive to amphetamine-induced locomotor hyperactivity (Polter et al., 2010). Studies using haploinsufficient GSK3 mice, GSK3 þ /−
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mice, reported significant decreases in amphetamine-induced locomotor activity. Increased amphetamine-induced hyperactivity was also observed in DISC1 mutant mice, which contain a mutation that impairs DISC1 ability to inhibit GSK3 (Lipina et al., 2010). In a mouse model over-expressing β-catenin in the CNS, reduced GSK3 activity significantly inhibited amphetamine-induced hyperactivity (Gould et al., 2007). ERK1 knockout mice were sensitized to amphetamine and displayed a heightened response in amphetamine-induced locomotor activity (Engel et al., 2009). Lithium administration normalized these amphetamine-induced behaviors, resulting in responses comparable to wild-type mice. Similar lithium-mediated reductions in amphetamine-induced hyperactivity have been reported in Bcl-2 þ /− mice (Lien et al., 2008) and Omega-3 fatty acid deficient mice (McNamara et al., 2007). Lithium was initially reported to reduce cocaine-induced hyperactivity and stereotypic behaviors by several groups (Flemenbaum, 1977; Antelman et al., 1998). Since then, regulation by GSK3β has also been reported to reduce cocaine-induced dopamine-mediated hyperactivity (Miller et al., 2009; Nwaneshiudu and Unterwald, 2010). Inhibition of GSK3β, via valproate or SB216763, a potent and selective ATP-competitive inhibitor of GSK3, administration, reduced cocaine-mediated locomotor activity and stereotypic behaviors (Miller et al., 2009) and the nucleus accumbens (Miller et al., 2009) and caudate putamen (Nwaneshiudu and Unterwald, 2010) were identified as key areas for this regulation. Collectively, these works establish that GSK3 promotes dopamine-mediated locomotor hyperactivity behaviors.
4. Transgenic mice and disease-associated hyperactivity The absence of lithium-mediated effects in wild-type rodent locomotor activity heightens interest in the reduced locomotor activity induced by lithium in transgenic mice that exhibit increased locomotor activity. Lithium has been reported to reduce locomotor activity in several transgenic and disease associated rodent models (Jope, 2011), including sleep-deprived rats (Gessa et al., 1995), rats administered ouabain (Jornada et al., 2011; Gao et al., 2011), mouse knockouts of the kainate receptor subunit GluR6 (Shaltiel et al., 2008), mouse knockouts of the Fmr1 gene that model Fragile X Syndrome (Yuskaitis et al., 2010), diacylglycerol kinase β knockout mice (Kakefuda et al., 2010), and mouse knockouts of the AMPA receptor GluA1 subunit (Fitzgerald et al., 2010). 4.1. Bipolar disorder Bipolar disorder (BD) is characterized by alternating episodes of mania and depression. Research focusing on genetic contributors to BD pathology identified glutamate receptor ionotropic kainite 2 (GRIK2), which encodes for the glutamate receptor 6 (GluR6) subunit of the kainate receptor, as a potential target for therapy (Shaltiel et al., 2008). Using GluR6 KO mice, Shaltiel et al. (2008) showed increased spontaneous (basal) locomotor activity, increased home cage general and exploratory activity, increased amphetamine-induced activity, and increased aggression. GluR6 KO mice administered lithium displayed significantly decreased spontaneous locomotor activity and aggression. There were no significant differences observed in wild-type mice after lithium treatment, again highlighting the specificity of GSK3-mediated effects on hyperactive, but not normal, behaviors. Diacylglycerol kinase β (DGKβ) has also been identified as a genetic contributor to BD pathology, with splice variants contributing to disease onset (Caricasole et al., 2002). Using DGKβ KO mice as the experimental BD model, Kakefuda et al. (2010) reported increased hyperactivity, decreased anxiety, and increased risk taking behavior
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M.A. Mines / European Journal of Pharmacology 708 (2013) 56–59
AMPH
DA
D2 activation
-arrestin P-Thr308
(active)
Ser21/9
Akt
GSK3 / Li+
PP2Ac
GSK3 /
Ser21/9
-arrestin
GSK3 /
PP2Ac Akt
-P
P-Ser21/9 GSK3 /
(active)
(inactive)
(active)
-P P-Ser21/9
GSK3 /
GSK3 /
-arrestin PP2Ac
-a rrestin PP2Ac
Akt
(inactive) -P
-P
Akt
GSK3 /
(active)
(inactive)
HYPERACTIVITY hyperactivity Fig. 1. GSK3 is involved in formation, stabilization, and activity of the β-arrestin/Akt/PP2Ac/GSK3 complex. (A) Stimulant administration increases DA release, activation of D2 receptors and promotes the association of β-arrestin with active GSK3 (unphosphorylated) and active Akt (phosphorylated). PP2Ac is also recruited to dephosphorylate Akt, thereby inactivating Akt, preventing Akt-mediated inhibition (phosphorylation) of GSK, and promoting hyperactivity-associated behaviors. (B) Inhibition of GSK3 has no effect on GSK3-β-arrestin association but promotes decreased association of Akt with PP2Ac, thereby preventing PP2Ac-mediated inactivation (dephosphorylation) of Akt. Active Akt (phosphorylated) inhibits GSK3 (phosphorylated) and decreases hyperactivity.
in DGKβ KO mice, as compared wild-type mice. Lithium had no effect on locomotor activity of wild-type mice, but significantly reduced DGKβ KO mice hyperactivity and normalized anxiety and risk-related behaviors. DGKβ KO mice displayed decreased phosphorylation of Akt and GSK3β in the cortex, indicative of decreased activity of Akt and increased GSK3β activity. Lithium treatment normalized phosphorylation profiles of both enzymes, with post-treatment levels resembling wild-type mice. Studies of animal models of mania have identified a correlation between sleep deprivation and hyperactivity, specifically during manic-like episodes (Plante and Winkelman, 2008). Gessa et al. (1995) reported that lithium treatment during times of sleep deprivation, insomnia and hyperactivity, significantly reduced sleep latency and decreased locomotor activity. Lithium administered alone or in combination therapies has been reported to decrease paradoxical sleep-induced (PSD) hyperactivity in a mouse model of mania (Armani et al., 2012). Collectively, these studies, and others, support a role for lithium treatment in reducing hyperactivity and increasing sleep. 4.2. Fragile X syndrome Fragile X syndrome (FXS) is the most common cause of inherited developmental intellectual impairment. Caused by a loss of expression of the fragile X mental retardation-1 (Fmr1) gene, FXS is characterized by subsequent loss of expression of fragile X mental retardation protein (FMRP). In an effort to identify therapeutics beneficial to FXS patients, Fmr1 knockout mouse and Drosophila models are commonly used, which display several FXS-
and autism-relevant behavioral phenotypes, including hyperactivity (Bakker et al., 1994). Detailed analysis of FXS mice (Fmr1 KO mice) revealed an impairment in the inhibitory serine-phosphorylation, but not total levels, of both GSK3 isoforms, suggesting increased activity of GSK3 (Mines et al., 2009; (Yuskaitis et al., 2010). Inhibition of GSK3, via lithium treatment, increased inhibitory serine-phosphorylation in Fmr1 knockout mice, comparable to wild-type mice. As locomotor hyperactivity is one of the more robust phenotypes of FXS mice, research has highlighted a specific role for GSK3 regulation in this behavior. (Yuskaitis et al., 2010) reported ameliorated hyperactivity phenotypes, including distance traveled and average center square behaviors, in the open-field paradigm after inhibition of GSK3 with chronic lithium treatment.
5. Conclusion Overall, this review highlights a role for GSK3 in several hyperactivity-associated pathologies and confirms the importance of GSK3 regulation, via phosphorylation and genetic manipulation, in symptom amelioration. Although lithium treatment was commonly used as a GSK3 inhibitor, it is important to note that lithium's actions may not be exclusively mediated by GSK3 inhibition and that the use of more specific GSK3 inhibitors is important in confirmatory studies. These findings reviewed here collectively suggest the presence of an alternative therapeutic target, GSK3, in the efforts to cure, treat, and diminish hyperactivity and associated behaviors in patients.
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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Perspective
Hyperactivity: Glycogen synthase kinase-3 as a therapeutic target Marjelo A. Mines n Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 14 December 2012 Received in revised form 15 February 2013 Accepted 24 February 2013 Available online 14 March 2013
The diagnosis of hyperactivity-associated disorders has increased within the past few years. The prevalence of hyperactivity-associated disorders is indicative of the need to more fully understand the underlying causes and to develop improved therapeutic interventions. There is increasing evidence that glycogen synthase kinase-3 (GSK3) mediates locomotor hyperactivity in a number of animal models, and therefore may be a potential target for therapeutic intervention in hyperactivity-associated behaviors. In this review, we discuss 1) the effect of manipulations of GSK3 in the absence of drugs and disorders on locomotor activity, 2) the role of GSK3 in drug-induced hyperactivity in rodents, and 3) regulation of locomotor activity by GSK3 in transgenic mouse models related to specific disorders. These studies link GSK3 regulation and activity to hyperactivity-associated behaviors and disease pathologies. & 2013 Elsevier B.V. All rights reserved.
Keywords: Amphetamine Attention-deficit/hyperactivity disorder Glycogen synthase-kinase 3 Locomotor hyperactivity Stimulants
1. Introduction Within the last five years, the diagnosis of disorders involving a hyperactivity component, such as bipolar disorder and attention deficit/hyperactivity disorder (ADHD), has become increasingly common, particularly in young people. The prevalence of hyperactivityassociated disorders is indicative of the need to more fully understand the underlying causes and to develop improved therapeutic interventions. Current therapies for hyperactivity disorders include stimulantbased medications, antidepressants, mood stabilizers, and psychotherapy (behavior modification therapy) (Center for Disease Control, 2010). Recently there is increasing evidence that inadequately controlled glycogen synthase kinase-3 (GSK3) underlies hyperactivity in a number of animal models, and thus may be a potential target for therapeutic intervention in hyperactivityassociated behaviors. GSK3 is a serine/threonine kinase first identified as an enzyme involved in glycogen synthesis, specifically by phosphorylating glycogen synthase. GSK3 has since been found to regulate over 50 substrates (Jope and Johnson, 2004). Accordingly, GSK3 regulates many fundamental processes, including development, cell structure, microtubule dynamics, gene expression, and cell survival (Frame and Cohen, 2001; Grimes and Jope, 2001). GSK3 exists as two isoforms, GSK3α and GSK3β (Woodgett, 1990), which often, but not exclusively, share functions (McManus et al., 2005; Polter and Li, 2011; Lal et al., 2012). GSK3 is constitutively partially active in cells. Therefore, input signals
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regulate GSK3 by decreasing or increasing its activity. The most prevalent mechanism regulating the activity of GSK3 is inhibition by phosphorylation on serine-21 of GSK3α and serine-9 of GSK3β. Several kinases mediate this serine-phosphorylation, which inhibits GSK3 activity (Jope and Johnson, 2004). Studies in rodents have linked GSK3 abnormalities to a surprisingly large and diverse number of conditions involving locomotor hyperactivity, in part by using GSK3 inhibitors such as lithium (Klein and Melton, 1996). Here, we review the information linking GSK3 to hyperactivityassociated behaviors and its involvement in disease pathologies.
2. Manipulations of GSK3 in the absence of drugs or disorders The most direct means to test the role of GSK3 in locomotor activity is to examine this relationship in mice with increased or decreased GSK3 levels or activity. Studies in healthy wild-type mice given GSK3 inhibitors most often report unaltered locomotor activity (Yuskaitis et al., 2010; O’Brien et al., 2011). Several rodent models containing genetic manipulations of GSK3 have been used to test GSK3 involvement in hyperactivity. Prickaerts et al. (2006) reported increased locomotor activity in mice expressing neuron-specific constitutively active GSK3, generated by serine-to-alanine mutations in the regulatory serines of both GSK3 isoforms, thereby inhibiting serine-mediated phosphorylation and preventing inhibition of GSK3. Mice lacking a functional GSK3α gene, resulting in the absence of GSK3α, displayed reduced open-field locomotor activity and reduced aggression (Kaidanovich-Beilin et al., 2009). GSK3 gene polymorphisms have been reported to be associated with the risk and pathology of ADHD. Shim et al. (2012) reported
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that incidence of the −1727 A/T single nucleotide polymorphism (SNP) of GSK3β gene was increased in ADHD patients. This finding bolstered a link between GSK3 and hyperactivity, specifically in ADHD, but warrants further study to identify the mechanism.
3. Drug-induced hyperactivity The most well-established link between activation of GSK3 and locomotor activity in rodents is in the dopamine 2 (D2) receptormediated responses to stimulants, such as amphetamine. Altered dopaminergic activity has been linked to neurological diseases, such as ADHD, schizophrenia, and Parkinson's disease (Carlsson, 2001; Gainetdinov and Caron, 2003). Psychostimulants, such as methylphenidate and amphetamine, are commonly used therapeutic options for ADHD and reduce associated symptoms (Cantwell, 1996; Solanto, 2002; Olfson et al., 2003). These drugs target the dopaminergic system via regulation of intracellular signaling mediated by the D1 and D2 families of dopamine receptors. In wild-type mice, inhibition of GSK3 decreased amphetamineinduced hyperactivity (Mines et al. 2013, Beaulieu et al., 2004, 2005, 2007). Administration of lithium, and other GSK3 inhibitors, attenuated amphetamine-induced hyperactivity behaviors in mice (Beaulieu et al., 2004, Kozikowski et al., 2007; Kalinichev and Dawson, 2011; Enman and Unterwald, 2012). Recently, research has established a link between dopamine receptors and signal mechanisms involving GSK3 (Beaulieu et al., 2009; DeFea, 2011; Shenoy and Lefkowitz, 2011). Acute treatment with stimulants causes a rapid increase in locomotor activity in rodents. The locomotion-inducing effect of amphetamine is mediated by activation of GSK3 (Beaulieu et al., 2004; Beaulieu et al., 2007). Akt, also known as Protein Kinase B (PKB), inhibits GSK3 activity through increases in inhibitory serine-phosphorylation of serine21-GSK3α and serine-9-GSK3β (Doble and Woodgett, 2003; Jope and Johnson, 2004). Both acute and long term amphetamine and methylphenidate administration decreased inhibitory serinephosphorylation of GSKα and GSK3β in the striatum by decreasing the activating phosphorylation of Akt on threonine-308-Akt (Mines and Jope, 2012; Beaulieu et al., 2004; Beaulieu et al., 2007). Stimulation of D2 receptors modulates the regulatory phosphorylation of GSK3 and Akt by altering the β-arrestin-2/ Akt/protein phosphatase 2, catalytic subunit α (PP2Ac)/GSK3 complex (Beaulieu et al., 2008). D2-mediated activity promotes the association of β-arrestin with active GSK3 (unphosphorylated) and active Akt (phosphorylated) (Fig. 1A). PP2Ac is recruited to dephosphorylate Akt, thereby inactivating Akt and preventing Aktmediated inhibition (phosphorylation) of GSK. Beaulieu et al. (2004, 2008, 2011) showed that regulation of this complex is required for amphetamine-induced locomotor hyperactivity. O’Brien et al. (2011) also examined the association of GSK3, β-arrestin, and Akt. In striatal homogenates from wild-type mice, GSK3 inhibitors promoted decreased association of Akt with PP2Ac and β-arrestin (Fig. 1B), suggesting that active GSK3 is required for complex formation. Conversely, increased Akt-PP2Ac association was found in GSK3 over-expressing mice, PrpGsk3β mice. While lithium treatment significantly decreased the association of Akt and PP2Ac in wild-type mice, it had no effect on Akt-PP2Ac association in PrpGsk3β mice, suggesting the need for GSK3 for complex stabilization (O’Brien et al., 2011). The association of Akt and PP2Ac in Gsk3β þ /− mice was identical to wild-type mice treated with lithium, showing decreased association. Cumulatively, these reports establish GSK3 as a key contributor to the formation, stability, and activity of this complex. Mice expressing constitutive activation of GSK3 are hypersensitive to amphetamine-induced locomotor hyperactivity (Polter et al., 2010). Studies using haploinsufficient GSK3 mice, GSK3 þ /−
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mice, reported significant decreases in amphetamine-induced locomotor activity. Increased amphetamine-induced hyperactivity was also observed in DISC1 mutant mice, which contain a mutation that impairs DISC1 ability to inhibit GSK3 (Lipina et al., 2010). In a mouse model over-expressing β-catenin in the CNS, reduced GSK3 activity significantly inhibited amphetamine-induced hyperactivity (Gould et al., 2007). ERK1 knockout mice were sensitized to amphetamine and displayed a heightened response in amphetamine-induced locomotor activity (Engel et al., 2009). Lithium administration normalized these amphetamine-induced behaviors, resulting in responses comparable to wild-type mice. Similar lithium-mediated reductions in amphetamine-induced hyperactivity have been reported in Bcl-2 þ /− mice (Lien et al., 2008) and Omega-3 fatty acid deficient mice (McNamara et al., 2007). Lithium was initially reported to reduce cocaine-induced hyperactivity and stereotypic behaviors by several groups (Flemenbaum, 1977; Antelman et al., 1998). Since then, regulation by GSK3β has also been reported to reduce cocaine-induced dopamine-mediated hyperactivity (Miller et al., 2009; Nwaneshiudu and Unterwald, 2010). Inhibition of GSK3β, via valproate or SB216763, a potent and selective ATP-competitive inhibitor of GSK3, administration, reduced cocaine-mediated locomotor activity and stereotypic behaviors (Miller et al., 2009) and the nucleus accumbens (Miller et al., 2009) and caudate putamen (Nwaneshiudu and Unterwald, 2010) were identified as key areas for this regulation. Collectively, these works establish that GSK3 promotes dopamine-mediated locomotor hyperactivity behaviors.
4. Transgenic mice and disease-associated hyperactivity The absence of lithium-mediated effects in wild-type rodent locomotor activity heightens interest in the reduced locomotor activity induced by lithium in transgenic mice that exhibit increased locomotor activity. Lithium has been reported to reduce locomotor activity in several transgenic and disease associated rodent models (Jope, 2011), including sleep-deprived rats (Gessa et al., 1995), rats administered ouabain (Jornada et al., 2011; Gao et al., 2011), mouse knockouts of the kainate receptor subunit GluR6 (Shaltiel et al., 2008), mouse knockouts of the Fmr1 gene that model Fragile X Syndrome (Yuskaitis et al., 2010), diacylglycerol kinase β knockout mice (Kakefuda et al., 2010), and mouse knockouts of the AMPA receptor GluA1 subunit (Fitzgerald et al., 2010). 4.1. Bipolar disorder Bipolar disorder (BD) is characterized by alternating episodes of mania and depression. Research focusing on genetic contributors to BD pathology identified glutamate receptor ionotropic kainite 2 (GRIK2), which encodes for the glutamate receptor 6 (GluR6) subunit of the kainate receptor, as a potential target for therapy (Shaltiel et al., 2008). Using GluR6 KO mice, Shaltiel et al. (2008) showed increased spontaneous (basal) locomotor activity, increased home cage general and exploratory activity, increased amphetamine-induced activity, and increased aggression. GluR6 KO mice administered lithium displayed significantly decreased spontaneous locomotor activity and aggression. There were no significant differences observed in wild-type mice after lithium treatment, again highlighting the specificity of GSK3-mediated effects on hyperactive, but not normal, behaviors. Diacylglycerol kinase β (DGKβ) has also been identified as a genetic contributor to BD pathology, with splice variants contributing to disease onset (Caricasole et al., 2002). Using DGKβ KO mice as the experimental BD model, Kakefuda et al. (2010) reported increased hyperactivity, decreased anxiety, and increased risk taking behavior
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AMPH
DA
D2 activation
-arrestin P-Thr308
(active)
Ser21/9
Akt
GSK3 / Li+
PP2Ac
GSK3 /
Ser21/9
-arrestin
GSK3 /
PP2Ac Akt
-P
P-Ser21/9 GSK3 /
(active)
(inactive)
(active)
-P P-Ser21/9
GSK3 /
GSK3 /
-arrestin PP2Ac
-a rrestin PP2Ac
Akt
(inactive) -P
-P
Akt
GSK3 /
(active)
(inactive)
HYPERACTIVITY hyperactivity Fig. 1. GSK3 is involved in formation, stabilization, and activity of the β-arrestin/Akt/PP2Ac/GSK3 complex. (A) Stimulant administration increases DA release, activation of D2 receptors and promotes the association of β-arrestin with active GSK3 (unphosphorylated) and active Akt (phosphorylated). PP2Ac is also recruited to dephosphorylate Akt, thereby inactivating Akt, preventing Akt-mediated inhibition (phosphorylation) of GSK, and promoting hyperactivity-associated behaviors. (B) Inhibition of GSK3 has no effect on GSK3-β-arrestin association but promotes decreased association of Akt with PP2Ac, thereby preventing PP2Ac-mediated inactivation (dephosphorylation) of Akt. Active Akt (phosphorylated) inhibits GSK3 (phosphorylated) and decreases hyperactivity.
in DGKβ KO mice, as compared wild-type mice. Lithium had no effect on locomotor activity of wild-type mice, but significantly reduced DGKβ KO mice hyperactivity and normalized anxiety and risk-related behaviors. DGKβ KO mice displayed decreased phosphorylation of Akt and GSK3β in the cortex, indicative of decreased activity of Akt and increased GSK3β activity. Lithium treatment normalized phosphorylation profiles of both enzymes, with post-treatment levels resembling wild-type mice. Studies of animal models of mania have identified a correlation between sleep deprivation and hyperactivity, specifically during manic-like episodes (Plante and Winkelman, 2008). Gessa et al. (1995) reported that lithium treatment during times of sleep deprivation, insomnia and hyperactivity, significantly reduced sleep latency and decreased locomotor activity. Lithium administered alone or in combination therapies has been reported to decrease paradoxical sleep-induced (PSD) hyperactivity in a mouse model of mania (Armani et al., 2012). Collectively, these studies, and others, support a role for lithium treatment in reducing hyperactivity and increasing sleep. 4.2. Fragile X syndrome Fragile X syndrome (FXS) is the most common cause of inherited developmental intellectual impairment. Caused by a loss of expression of the fragile X mental retardation-1 (Fmr1) gene, FXS is characterized by subsequent loss of expression of fragile X mental retardation protein (FMRP). In an effort to identify therapeutics beneficial to FXS patients, Fmr1 knockout mouse and Drosophila models are commonly used, which display several FXS-
and autism-relevant behavioral phenotypes, including hyperactivity (Bakker et al., 1994). Detailed analysis of FXS mice (Fmr1 KO mice) revealed an impairment in the inhibitory serine-phosphorylation, but not total levels, of both GSK3 isoforms, suggesting increased activity of GSK3 (Mines et al., 2009; (Yuskaitis et al., 2010). Inhibition of GSK3, via lithium treatment, increased inhibitory serine-phosphorylation in Fmr1 knockout mice, comparable to wild-type mice. As locomotor hyperactivity is one of the more robust phenotypes of FXS mice, research has highlighted a specific role for GSK3 regulation in this behavior. (Yuskaitis et al., 2010) reported ameliorated hyperactivity phenotypes, including distance traveled and average center square behaviors, in the open-field paradigm after inhibition of GSK3 with chronic lithium treatment.
5. Conclusion Overall, this review highlights a role for GSK3 in several hyperactivity-associated pathologies and confirms the importance of GSK3 regulation, via phosphorylation and genetic manipulation, in symptom amelioration. Although lithium treatment was commonly used as a GSK3 inhibitor, it is important to note that lithium's actions may not be exclusively mediated by GSK3 inhibition and that the use of more specific GSK3 inhibitors is important in confirmatory studies. These findings reviewed here collectively suggest the presence of an alternative therapeutic target, GSK3, in the efforts to cure, treat, and diminish hyperactivity and associated behaviors in patients.
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