The Journal of Neuroscience, December 17, 2008, 28(51):13952-13956; doi:10.1523/JNEUROSCI.4986-08.2008
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Brief Communications
Chronic G
s Signaling in the Striatum Increases Anxiety-Related Behaviors Independent of Developmental Effects
Christopher Favilla,1
Ted Abel,1 and
Michele P. Kelly1,2
Departments of 1Biology and 2Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104
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Abstract
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Current research in the field of anxiety disorders is largely receptor-centric, leaving intracellular pathways largely unexplored. G
s, the G-protein which stimulates adenylyl cyclase and L-type voltage-gated calcium channels, may be one intracellular molecule regulating anxiety-related behaviors as increased efficacy of Gs signaling has been noted in patient populations that suffer from anxiety. We report here anxiety-related behaviors in two lines of transgenic mice expressing a constitutively active isoform of Gs (or Gs*). The first line expressed Gs* throughout postnatal forebrain neurons, while the second line of mice conditionally expressed Gs* selectively in the striatum (Gs*str mice). In the open field, both lines of mice showed a significant preference for the periphery suggesting that expression of Gs* in the striatum alone was sufficient to produce an anxiogenic phenotype. In the light/dark box, Gs*str mice exhibited longer latencies to enter the light and spent significantly less time in the lit compartment. Similarly, Gs*str mice showed longer latencies to enter the open quadrants and spent less time in the open quadrants of the elevated zero maze. Interestingly, these anxiety-related phenotypes were largely unrelated to developmental effects as mice expressing the Gs*str transgene during development, but not at testing, were normal on most measures. These observations show that chronic Gs signaling in the striatum is sufficient to trigger anxiety-related behaviors largely independent of developmental effects and suggest the cAMP pathway or L-type voltage-gated calcium channels may be viable targets for future pharmacological intervention in the treatment of anxiety disorders.
Key words: GNAS; anxiety; panic disorder; striatum; cAMP; L-VGCC
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Introduction
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Anxiety disorders are estimated to have a lifetime prevalence rate in the United States of 31% (Kessler et al., 2007
). In addition to the psychological symptoms (e.g., irrational fear, worry, restlessness, and sleep disturbances) classically associated with anxiety disorders, patients show an increased risk for a variety of physical illnesses, including heart disease, obesity, and cancer (cf., Balon, 2006). Thus, anxiety disorders pose a threat to both the mental and physical well being of a large percentage of the population, greatly affecting quality of life and producing an economic burden (Hoffman et al., 2008).
Despite the widespread prevalence of anxiety disorders, the biochemical substrates underlying these pathological behavioral responses remain largely unknown. One potential intracellular mechanism contributing to anxiety disorders may be increased signaling through Gs, the G-protein that stimulates adenylyl cyclase (cf., Neves et al., 2002) and L-type voltage-gated calcium channels (VGCC) (Yatani and Brown, 1989; Lader et al., 1998). Gurguis and colleagues (1999) found increased efficacy of Gs signaling in neutrophils of drug-free patients with panic disorder as well as in polymorphonuclear leukocytes of patients with panic disorder (Gurguis et al., 1997). In addition, increased levels and/or efficacy of Gs have repeatedly been measured in peripheral and central measures from patients with bipolar disorder (Young et al., 1991, 1993, 1994; Avissar et al., 1997), a patient population with high rates of comorbid anxiety (cf., Oswald et al., 2007). Together, these data raise the possibility that chronic Gs signaling may contribute to anxiety-related phenotypes.
Given that disease-related symptoms are likely due to long term changes in neuronal function, we test here the behavioral effect of chronically increasing Gs signaling. To do so, we evaluated two lines of transgenic mice that express a constitutively active isoform Gs (Gs*). In the first line, forebrain-specific expression of Gs* was driven by the CaMKII promoter (see Fig. 1A) (Wand et al., 2001; Kelly et al., 2007, 2008). In the second line, conditional expression of Gs* was driven with the reversible tetracycline-regulated system (see Fig. 1B), which spatially restricted expression of the transgene to forebrain neurons and enabled expression of the transgene to be suppressed with administration of doxycycline (dox) (see Fig. 1C). By driving expression of our transgene with this reversible system, we were able to determine whether expressing Gs* during development was sufficient to alter anxiety-related behaviors in adults. By virtue of where in the genome the tetO construct randomly inserted, the new transgenic line showed Gs* expression enriched in the striatum consistent with increased cAMP levels being found only in this region (referred to hereafter as Gs*str mice; see Fig. 1). Thus, Gs*str mice impart enhanced temporal and spatial resolution relative to our initial line. Focusing on anxiety-related behaviors, we tested Gs* mice in the open field, light/dark box, and elevated zero maze. We show that, across all paradigms, Gs*str mice exhibited a significant increase in anxiety-related behaviors relative to control littermates and that this phenotype was largely independent of developmental effects.
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Materials and Methods
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Subjects
Transgenic mice were bred and group-housed in breeding colonies at the University of Pennsylvania in the hemizygous state on a C57BL/6J background. Transgenic mice express an isoform of the Gs protein subunit that is constitutively active due to a point mutation (Q227L), as previously described (Wand et al., 2001). This mutation prevents the hydrolysis of bound GTP and, in so doing, results in increased basal adenylyl cyclase activity in the brain (Wand et al., 2001; Kelly et al., 2007). CaMKII-Gs* mice (N12–13 onto C57BL/6J) were bred as previously described (Kelly et al., 2007, 2008). The tetO-Gs* transgene was microinjected into pronuclei from superovulated B6SJLF1/J mice by the Transgenic and Chimeric Mouse Facility at the University of Pennsylvania. The line reported here (line 1485, referred to as Gs*str mice) was then backcrossed onto C57BL/6J for 5–6 generations in the hemizygous state before being mated to CaMKII-tTA(B) mice (Mayford et al., 1996;N20+ on C57BL/6J). Only mice positive for both the tetO and CaMKII driven constructs express the Gs* transgene. The control group, then, includes wild-type mice (with neither construct), tetO-only mice and CaMKII-only mice. For experiments using doxycycline, 200 mg/kg was administered via the chow to both Gs*str and control littermates either 
2.5 weeks before test (i.e., Gs*str-dev mice) or from gestation through testing (i.e., for Gs*str-dox mice). This dose was chosen based on our previous experience that 40 mg/kg dox was insufficient to reliably suppress transgene expression in our tetracycline regulated Gswt mice (our unpublished observations). In situ hybridization confirmed that 2.5 weeks of dox was sufficient to suppress transgene expression (see Fig. 1D). Using transgene specific probes, animals are genotyped by Southern blot, but all experiments are conducted blind to genotype. For both lines, transgenic mice 2–5 months old were compared with sex-matched control littermates. All experiments were conducted in accordance with National Institutes of Health guidelines for animal care and use, and all experiments were approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania.
Behavior
Locomotor activity.
Locomotor activity was measured for 30 min in a 41 x 41 cm San Diego Instruments Open Field (Stein et al., 2006). The box was equipped with 16 x 16 motion detector beams (every 2.54 cm). Ambulations (breaks of two contiguous beams) and preference for the periphery (percentage of ambulations in outer two beams on all sides) were calculated.
Light/dark box.
Partiality to light versus dark was measured in a modified housing cage (Stein et al., 2006). Animals were introduced to the dark chamber and were allowed to explore the apparatus freely for 10 min. Latency to enter (operationally defined as the time when all four paws first crossed the threshold of the 6 x 6 cm opening) and the total time spent in the lit compartment were recorded.
Elevated zero maze.
Preference for walled versus exposed quadrants was measured in an elevated circular track (Stein et al., 2006). Animals were introduced to a walled quadrant and permitted to explore the elevated zero maze for 10 min. Latency to enter (operationally defined as time when all 4 paws first entered the open) and total time spent in the open quadrants were recorded.
Contextual fear conditioning.
Contextual fear conditioning was conducted as previously described (Kelly et al., 2008), by pairing a training context with a 1.5 mA footshock and measuring the level of freezing exhibited in the same context 24 h later (3 min session).
Prepulse inhibition.
Prepulse inhibition (PPI) was conducted as previously described (Kelly et al., 2007; Kanes et al., 2007), using prepulses 4–16 dB above a 68 dB background and a pulse of 120 dB and measuring the startle response with an accelerometer (San Diego Instruments).
Biochemistry
In situ hybridization and cAMP assays were conducted as previously described (Kelly et al., 2007, 2008). For biochemical experiments, animals were killed by cervical dislocation and brains were immediately harvested, hemisected (one half intact for in situ the other dissected for cAMP assays), and placed on dry ice. "Parahippocampal cortex" was defined as cortical regions overlying the hippocampus. Levels of cAMP were measured from a single hemisphere using a radioimmune competition assay kit (Perkin-Elmer). All animals were killed from the home cage.
Data analyses
Data were analyzed for effect of genotype by t test using Sigmastat (v. 2.03; Systat). In biochemical experiments, balanced groups of animals were raised at different times and killed on different days. Therefore, to control for any confounds due to day of killing, data for each group were normalized and expressed as a percentage of the control (CT) mean, as previously described (Kelly et al., 2007, 2008). Normalized data were then combined and analyzed for effects of genotype. Statistical outliers >2 SDs from the mean were removed from analyses. Significance was determined at p < 0.05. All values reported are means ± SEM.
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Results
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Gs*str mice showed increased cAMP levels in the striatum
Autoradiographic in situ hybridization showed transgene expression was more spatially restricted in the Gs*str mice (Fig. 1C) versus our original CaMKII-Gs* mice (Fig. 1B). Biochemical analyses show that Gs*str mice show elevated cAMP levels only in striatum (not cortex nor hippocampus) (Fig. 1E) (n = 5–9 per genotype; t(12) = 3.10, p = 0.009), as previously reported in CaMKII-Gs* mice (41% increase; Kelly et al., 2007). Developmental expression of Gs*str is not sufficient to cause permanent alterations in striatal cAMP levels, because Gs*str-dev mice show striatal cAMP levels equivalent to those of control littermates (Fig. 1F) (n = 7 per genotype; t(6) = 0.47, p = 0.657).
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Figure 1. Gs*str mice showed striatally enriched transgene expression and cAMP elevation restricted to the striatum. A, The tetracycline-regulated transgenic system used herein employs the CaMKII promoter to restrict expression of the transcription factor tTA to postnatal forebrain neurons. The tTA protein then binds the Tet promoter, activating transcription of the ligated transgene. Doxycycline impedes the ability of tTA to bind, thus preventing transcription. As such, the tetracycline system enables expression of a transgene to be suppressed. B, Autoradiographs for CaMKII-Gs* mice showed expression of the transgene throughout postnatal forebrain neurons (nonreversible). C, Autoradiographs for CaMKII-tTA/tetO-Gs* mice showed transgene expression enriched in the striatum (thus, referred to as Gs*str mice). D, Autoradiographs also showed that transgene expression within Gs*str mice is reversible with dox, as shown in a Gs*str-dev mouse (i.e., a mouse that expressed the transgene throughout development but received dox during adulthood). E, As previously measured in CaMKII-Gs* mice (Kelly et al., 2007), Gs*str mice showed significantly elevated cAMP levels (%CT pmol/mg protein) in the striatum. Gs*str showed no significant differences in hippocampal or cortical cAMP levels. F, The elevated striatal cAMP levels observed in adult Gs*str mice were not due to developmental effects, as evidenced by normal cAMP levels in Gs*str-dev mice. The asterisk (*) versus CT, p = 0.009. FCx, Frontal cortex; Hipp, hippocampus; PCx, parahippocampal cortex; Str, striatum.
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CaMKII-Gs* and Gs*str mice exhibited a significant preference for the periphery of an open field
To determine whether expressing Gs* in forebrain neurons would be sufficient to increase anxiety-related behaviors, we characterized our initial line of CaMKII-Gs* mice in an open field. Relative to wild-type mice (n = 7–8, per genotype), CaMKII-Gs* mice exhibited a higher percentage of ambulations in the periphery of the open field (t(13) = 2.28, p = 0.048) (Fig. 2A). In addition, CaMKII-Gs* mice showed significantly more ambulations overall (t(12) = 3.50, p = 0.004) (Fig. 2B). These results suggest that Gs* expression is sufficient to cause hyperlocomotion and an increase in anxiety-related behavior.
To further isolate where in the brain and when (i.e., development vs adulthood) Gs* acts to influence locomotor and anxiety-related behavior, we also tested Gs*str and control littermates in the open field (n = 14–18 per genotype). Consistent with the observations above, Gs*str mice showed a greater preference for the periphery of the open field (t(30) = 3.19, p = 0.003) (Fig. 2a). In contrast to the CaMKII-Gs* line, however, Gs*str mice displayed no difference in total ambulations relative to control littermates (Fig. 2B), showing the effect of Gs* signaling on the anxiety-related phenotype in the open field is dissociable from the effect on hyperactivity.
Gs*str mice showed anxiety-related phenotypes in a light/dark box and an elevated zero maze
To determine whether the Gs*-induced anxiety-related phenotype observed above in the open field would extend to additional anxiety-related paradigms, we tested Gs*str mice and control littermates in the light/dark box and elevated zero maze paradigms. In the light/dark box, Gs*str mice exhibited a longer latency to enter the lit chamber relative to their control littermates (n = 7–11 per genotype; t(16) = 3.62, p = 0.002) (Fig. 3A). Additionally, Gs*str mice spent significantly less time in the lit compartment relative to control littermates (t(16) = 2.27, p < 0.037) (Fig. 3B). This pattern of behavior is paralleled in the elevated zero maze, where Gs*str mice showed a longer latency to enter the open quadrants (n = 7–10, per genotype; t(15) = 3.01, p = 0.009) (Fig. 3C) and spent less total time in the open quadrants relative to control littermates (t(14) = 2.99, p = 0.01) (Fig. 3D). These behaviors confirm the hypothesis that chronically increasing Gs* signaling is sufficient to increase anxiety-related phenotypes and suggest the effect is localized to the striatum.
Anxiety-related phenotypes observed in Gs*str mice were largely unrelated to developmental effects
Next we determined whether the anxiety-related phenotypes observed in adult Gs*str mice were due to developmental effects. To do so, we tested adult Gs*str mice that experienced transgene expression throughout development, but not at the time of adulthood testing due to doxycycline administration (referred to as Gs*str-dev mice). Gs*str-dev mice did not exhibit a significant preference for the periphery of an open field relative to control littermates (Fig. 2A; n = 7 per genotype; t(12) = 1.52, p = 0.154). Similarly, Gs*str-dev mice showed no significant difference in the latency to enter the lit compartment of the light/dark box (Fig. 3A) (n = 7, per genotype; t(12) = 0.77, p = 0.456). In contrast, however, Gs*str-dev mice did spend significantly less time in the light in total (Fig. 3B) (t(12) = 2.58, p = 0.024). This effect observed in Gs*str-dev mice was specifically due to developmental expression of the transgene (as opposed to a confounding effect of transgene insertion) because Gs*str mice administered dox throughout life (i.e., that never expressed the transgene; Gs*str-dox) showed no difference with respect to latency to enter the lit chamber (Fig. 3A) (n = 4 per genotype; t(6) = 0.75, p = 0.48) nor total time spent in the light (Fig. 3B) (t(6) = 0.30, p = 0.77). In the elevated zero maze, Gs*str-dev mice showed no significant difference in the latency to enter the open quadrants (Fig. 3C) (n = 7 per genotype; t(12) = 1.46, p = 0.172) nor in the total time spent in the open quadrants (Fig. 3D) (t(12) = 1.96, p = 0.074).
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Discussion
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Here, we showed that chronically increasing Gs signaling in the forebrain triggers an increase in anxiety-related behaviors in the open field, light/dark box, and elevated zero maze. The fact that chronic Gs signaling increases anxiety-related behaviors largely independent of developmental effects suggests that such anxiety-related pathophysiology is readily reversible in the adult. These observations are particularly relevant to patients with panic disorder, in whom increased efficacy of Gs signaling has been noted (Gurguis et al., 1997, 1999).
Data presented here suggest that the effect of Gs* on anxiety-related behaviors is localized to the striatum. This conclusion is based on the fact that Gs*str mice, which exhibited increased anxiety-related behaviors, showed cAMP changes in striatum but not in hippocampus nor cortex. Further, Gs*str mice showed intact contextual fear conditioning and PPI (Fig. 4), behaviors influenced by chronic Gs signaling in the hippocampus and cortex (Kelly et al., 2007, 2008). Although studies here do not rule out completely the possibility that Gs* is acting elsewhere in the brain, a striatally localized effect of Gs* on anxiety would be consistent with an extensive literature implicating this brain region as key to the circuitry underlying anxiety-related behaviors and pathologies [e.g., for panic disorder, see Reiman et al. (1989), Yoo et al. (2005); for social anxiety disorder, cf., Mathew and Ho (2006); for bipolar disorder, see Konarski et al. (2008), Killgore et al. (2008)]. Dysfunction within the dorsal striatum, in particular, may disrupt processing of safety signals that would otherwise decrease expression of fearful or anxiety-related behaviors (Rogan et al., 2005).
It remains to be determined through which downstream target Gs* elicits an anxiogenic profile. Chronically increasing cAMP signaling could increase anxiety, by virtue of decreasing GABA functionality (Moss et al., 1992; Shekhar et al., 2003; Kalueff and Nutt, 2007). Although increasing cAMP signaling acutely appears to reduce anxiety-related behaviors in rodents (Silvestre et al., 1999; Barrot et al., 2002; Masood et al., 2008), chronically increasing cAMP signaling has the opposite effect. Genetic deletion of the cAMP-degrading enzyme Phosphodiesterase 4B or overexpression of the striatally enriched cAMP-producing enzyme adenylyl cyclase 5, increases anxiety-related behavior in mice (Kim et al., 2008; Zhang et al., 2008). In addition, genetic deletion of 5HT1A receptors, which couple negatively to adenylyl cylase via Gi, increases anxiety-related behaviors in mice, and a reduction in 5HT1A receptors has been measured in patients with social anxiety disorder (cf., Lesch et al., 2003). Increased activity of L-type VGCCs could also contribute to Gs*-induced increases in anxiety as they play a role in the anxiogenic effects associated with amphetamine and nicotine administration (Biala and Budzynska, 2006; Bia
a and Kruk, 2007; Biala and Kruk, 2008). Further, calcium channel blockers have been proposed as a novel class of anxiolytics, particularly for treatment of panic disorder (Balon and Ramesh, 1996). As such, we hypothesize that Gs*-induced anxiety is likely due to the chronic nature of the cAMP upregulation and/or increased activation of L-type VGCCs. Our results identify Gs as an intracellular signaling molecule regulating the anxiety response, suggesting Gs or it downstream effectors may prove effective therapeutic targets in the treatment of anxiety disorders.
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Footnotes
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Received Oct. 15, 2008;
accepted Nov. 11, 2008.
This work was supported by Tourettes Syndrome Association (M.P.K.), National Institute of Mental Health (NIMH) Grant T32 MH019112 [to M.P.K., R. Gur, Principal Investigator (P.I.)], and Merck, Whitehall, and Packard Foundations as well as NIMH Grants R01 MH60244, NIA R01 AG18199, and P50 MH 6404501 (Project 3 to T.A.; R. Gur, Conte Center P.I.). M.P.K. is currently employed by Wyeth Research. We thank Dr. Raquel Gur for helpful discussions and Dr. Jean Richa for efforts in generating our transgenic mice.
Correspondence should be addressed to Michele P. Kelly at her present address: Wyeth Research, Neuroscience/Room 1806, 865 Ridge Road, Monmouth, NJ 08852. Email: kellym22{at}wyeth.com
Copyright © 2008 Society for Neuroscience 0270-6474/08/2813952-05$15.00/0
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Abstract
Introduction
