- Email: [email protected]
GABAB receptors, depression, and stress resilience
C H A P T E R
5 GABAB receptors, depression, and stress resilience: a tale of two isoforms Olivia F. O’Leary1, 2, John F. Cryan1, 2 1
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; 2APC Microbiome Institute, University College Cork, Cork, Ireland
Introduction In the central nervous system, gamma-aminobutyric acid (GABA) acts on two types of receptors: ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors. GABAA receptors are ligand-gated ion channels while GABAB receptors are G-protein-coupled receptors. GABAB receptors are found presynaptically where they function as either autoreceptors limiting the release of GABA or as heteroreceptors inhibiting the release of glutamate. However, these receptors are also found postsynaptically where they induce slow inhibitory postsynaptic currents (Cryan and Kaupmann, 2005; Bettler et al., 2004). Functional GABAB receptors are heterodimers of GABAB1 and GABAB2 subunits, and the GABAB1 subunit is expressed as several isoforms (Lee et al., 2010; Fritschy et al., 1999). The GABAB1a and GABAB1b isoforms are the predominant subunit isoforms that are expressed in the brain, whereby the GABAB1b subunit isoform is predominantly localized postsynaptically, whereas the GABAB1a subunit isoform is mainly found presynaptically (Fritschy et al., 1999; Gassmann and Bettler, 2012; Vigot et al., 2006). In dendrites, GABAB1a localizes to glutamatergic terminals for heteroreceptor function, whereas GABAB1b localizes to spines opposing glutamate release sites, thus affecting presynaptic or postsynaptic inhibition (Gassmann and Bettler, 2012). Structurally, these two isoforms differ only by the presence of a sushi domain in the N-terminus of the GABAB1a receptor subunit isoform, which is thought to increase surface stability of GABAB(1a, 2) receptors and promote their axonal localization (Gassmann and Bettler, 2012; Hannan et al., 2012). Interest in the role of the GABAB receptor in stress resilience began 30 years ago, when a potential role for the GABAB receptor in the pathophysiology and treatment of the Stress Resilience https://doi.org/10.1016/B978-0-12-813983-7.00005-7
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Copyright © 2020 Elsevier Inc. All rights reserved.
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5. GABAB receptors, depression, and stress resilience: a tale of two isoforms
stress-related disorder, depression, was first reported (Pilc and Lloyd, 1984). Since then, many preclinical studies have reported a reciprocal but complex relationship between stress-related psychiatric disorders such as depression and anxiety with the GABAB receptor as outlined in the following sections.
The impact of stress-related psychiatric disorders and their treatments on GABAB receptor density, gene expression and function Effects of antidepressants on GABAB receptor density in rodents The first hint that the GABAB receptor may play a role in stress-related responses came from receptor binding studies in the early 1980s, which examined the effects of antidepressant treatments on GABAB receptor density (Pilc and Lloyd, 1984). Since then, many other studies have reported that this receptor is affected by several different antidepressant treatments although some conflicting and brain region-dependent results have also been reported (Felice et al., 2016; Ghose et al., 2011; Cryan and Slattery, 2010; Enna and Bowery, 2004). It was reported that chronic but not acute treatment with the antidepressants amitriptyline, desipramine, or citalopram increased GABAB receptor-binding sites (i.e., receptor density) in the rat frontal cortex (Pilc and Lloyd, 1984). These findings were reproduced in a later study, which also reported that other antidepressant treatments including fluoxetine, mianserin, trazodone, and repeated electroconvulsive shocks upregulated GABAB receptor binding in the rat frontal cortex (Lloyd et al., 1985). Such effects of antidepressants on GABAB receptor binding seemed to be region dependent and were not apparent in the rat hippocampus (Lloyd et al., 1985). Chronic treatment with the antidepressant imipramine was also shown to increase GABAB receptor binding in the mouse cortex (Suzdak and Gianutsos, 1986). However, opposing data have also been reported. For instance, Pratt and Bowery (1993) reported that although desipramine increased GABAB receptor binding in the rat frontal cortex, neither paroxetine nor amitriptyline had any effect (Pratt and Bowery, 1993). Similarly, a lack of effect of desipramine, imipramine, and tranylcypromine on frontal cortex GABAB receptor binding has been reported by others (Cross and Horton, 1987, 1988; McManus and Greenshaw, 1991). On the other hand, the antidepressants desipramine and imipramine have been shown to reverse the reduction in frontal cortex GABAB receptor that is induced by learned helplessness, thus suggesting that antidepressants may affect GABAB receptor density not only under basal conditions but also in depression-like states (Martin et al., 1989).
Effects of antidepressants on GABAB receptor function in rodents These findings of antidepressant-induced increases in GABAB receptor density in the cortex are consistent with findings that GABAB receptor function is increased following various antidepressant treatments. Indeed, it has been reported that imipramine-induced increases in GABAB receptor density were accompanied by enhanced receptor function as shown by the potentiation of baclofen (a GABAB receptor agonist)-induced adenylate cyclase activity in the mouse cerebral cortex (Suzdak and Gianutsos, 1986).
The impact of stress-related psychiatric disorders and their treatments on GABAB receptor density, gene expression and function
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Repeated treatment with the antidepressant tranylcypromine has also been reported to enhance GABAB receptor function in the rat cerebral cortex as measured by baclofenstimulated GTPgS binding (Sands et al., 2003). Similarly, chronic treatment with amitriptyline, desipramine, mianserin, or electroconvulsive shock increased GABAB receptoremediated modulation of serotonin release in the mouse frontal cortex (Gray and Green, 1987). In contrast to all of these findings, however, one study reported that antidepressants including desipramine and imipramine do not alter GABAB receptor function in the cerebral cortex (Szekely et al., 1987). Interestingly, 7 days treatment with the antidepressants tranylcypromine, phenelzine, or desipramine (but not fluoxetine) increased GABAB receptor function in the rat hippocampus (Sands et al., 2004). This suggests that although antidepressants affect GABAB receptor density in the frontal cortex but not hippocampus (Lloyd et al., 1985), these drugs can affect receptor function in both the hippocampus and the frontal cortex (Lloyd et al., 1985; Sands et al., 2004). However, it should also be noted that the direction of change of antidepressant effects on GABAB receptor function may be region dependent, as it has been reported that chronic fluoxetine treatment reduced GABAB receptoreinduced GIRK responses in the rat dorsal raphe nucleus (DRN) (Cornelisse et al., 2007).
Clinical evidence of altered GABAB receptor density and function in depression and the antidepressant response All of this preclinical evidence is supported by a growing body of clinical evidence of GABAB receptor dysfunction in depression (for review, see Felice et al., 2016; Ghose et al., 2011). Indeed, recent clinical neurophysiology studies suggest that deficits in GABAB receptors may play a role in major depression and the antidepressant response to fluoxetine (Levinson et al., 2010; Croarkin et al., 2014). In addition, the induction of growth hormone release by the GABAB receptor agonist baclofen is blunted in depressed patients (O’Flynn and Dinan, 1993; Marchesi et al., 1991). Moreover, it has been reported that the GABAB2 receptor subunit is upregulated in cortical and subcortical brain regions in depressed suicide victims compared with those without a history of depression (Klempan et al., 2009). Similarly, a 50% increase in GABAB2 subunit gene expression was reported in the dentate gyrus of the hippocampus in depressed individuals (Ghose et al., 2011). However, this upregulation is not reflected in earlier receptor binding studies in which similar GABAB receptorebinding profiles in the frontal or temporal cortices and the hippocampus had been reported in depressed suicide victims and controls (Cross et al., 1988) and in the frontal cortex of suicide victims and controls (Arranz et al., 1992).
Alterations in GABAB receptor density and function in animal models of stress and depression Considering the relatively strong evidence for a potential role of the GABAB receptor in depression and the response to antidepressants, it is somewhat surprising that only a limited number of preclinical studies have measured GABAB receptor expression and
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function in animal models of depression and stress. It has been reported that GABAB receptor binding in the frontal cortex is reduced in the rat learned helplessness model of depression (Martin et al., 1989). On the other hand, however, chronic restraint stress (7 days) had no effect on GABAB receptor activity in the cerebral cortex as measured by baclofen-stimulated GTPgS binding (Sands et al., 2003). Similarly, social stress did not affect GABAB receptoremediated GIRK currents in the rat DRN (Cornelisse et al., 2007). In summary, most preclinical studies have reported that chronic treatment with several different antidepressants increases GABAB receptor density and activity particularly in the cortex. In support, clinical studies suggest that deficits in GABAB receptor function may play a role in major depression and the antidepressant response to fluoxetine; however, only a limited number of clinical studies have actually been conducted. Although no differences in GABAB receptorebinding profiles have been reported in the frontal and temporal cortices of the suicide brain, increased expression of the GABAB2 receptor subunit has been reported in the hippocampus and cortex of depressed suicide victims. Taken together, these preclinical and clinical studies on GABAB receptor density and activity suggest a role for the GABAB receptor in antidepressant action and perhaps a more indirect or limited role in the pathophysiology of stress and depression. Nevertheless, as outlined in the following sections, it is clear that altering GABAB receptor activity regulates depression and anxietylike behaviors and behavioral responses to stress.
Effects of GABAB receptor modulation on depression-like behaviors There is a large body of convincing preclinical evidence that pharmacological or genetic manipulation of the GABAB receptor affects anxiety-, depression-, and antidepressantrelated behaviors (Cryan and Kaupmann, 2005; Felice et al., 2016; Cryan and Slattery, 2010). Mice with null mutations of either the GABAB1 or GABAB2 receptor subunits demonstrate an antidepressant-like behavioral phenotype as indicated by reduced immobility in the forced swim test (FST; Mombereau et al., 2004, 2005). Moreover, GABAB receptor antagonists exert antidepressant-like effects in the FST, and in the learned helplessness, olfactory bulbectomy, and chronic mild stress paradigms (reviewed in Felice et al., (2016)). Specifically, the GABAB receptor antagonists CGP56433A, CGP51176, CGP5633A, CGP36742, and SCH50911 have all been shown to induce antidepressant-like behavior in the FST in rats or mice (Mombereau et al., 2004; Slattery et al., 2005; Nowak et al., 2006; Frankowska et al., 2007; Felice et al., 2012). GABAB receptor antagonists are also effective in other rodent models of depression and antidepressant activity including the olfactory bulbectomy model (CGP36742 and CGP51176) (Nowak et al., 2006), chronic mild stress (CGP51176) (Nowak et al., 2006), and learned helplessness model (CGP36742) (Nakagawa et al., 1999). On the other hand, it is positive allosteric modulators (PAMs) of GABAB receptors that exert anxiolytic effects in tests of innate anxiety although PAMs do not exert any effects in conditioned fear paradigms (Frankowska et al., 2007; Sweeney et al., 2013; Li et al., 2015; Cryan et al., 2004). Taken together, it is clear that reducing GABAB receptor function has antidepressant-like effects, whereas positive allosteric modulation of the receptor has anxiolytic effects.
The role of GABAB1 receptor subunit isoforms in stress resilience
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The role of GABAB1 receptor subunit isoforms in stress resilience Although it is clear that pharmacological modulation of GABAB receptors can influence depression and anxiety-like behaviors, relatively few studies have examined their effects in the behavioral responses to chronic stress. Nevertheless, it has been reported that the GABAB receptor antagonist, CGP51176, prevented anhedonia in the chronic mild stress paradigm (Nowak et al., 2006). More recently, we have used GABABð1aÞ-=- and GABABð1bÞ-=- mice as tools to delineate the roles of specific GABAB1 receptor subunit isoforms in depression and anxiety-related behaviors as well as in resilience and susceptibility to stress-induced changes in these behaviors. Indeed, we recently reported that GABAB1a and GABAB1b receptor subunit isoforms differentially regulate stress resilience in both male and female mice (O’Leary et al., 2014) (Fig. 5.1). Specifically, male GABABð1aÞ-=- mice were more susceptible, whereas male GABABð1bÞ-=- mice were more resilient to chronic social defeat stress (O’Leary et al., 2014). In the social interaction test, social defeat stress decreased social interaction to a greater extent in GABABð1aÞ-=- mice when compared with wild-type mice. On the other hand, mice lacking the GABABð1bÞ-=- isoform were resilient to this stress-induced social avoidance. Moreover,
FIGURE 5.1 Summary of the main differences between GABABð1aÞ-=- mice in their response to stress and potential underlying mechanisms of stress resilience in GABABð1bÞ-=- mice. CORT, corticosterone; DRN, dorsal raphe nucleus; FST, forced swim test; MS, maternal separation; NAcc, nucleus accumbens; SDS, social defeat stress; TST, tail suspension test.
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social defeat stress induced anhedonia in GABABð1aÞ-=- mice as measured by reduced preference to drink a sweet solution of saccharin over water, whereas GABABð1bÞ-=- mice were resilient to this measure of stress-induced anhedonia. In an independent cohort of mice, we also examined the impact of early-life stress on depression and anxiety-related behaviors in adulthood and using a model amenable to both male and female mice (O’Leary et al., 2014). To this end, we used unpredictable maternal separation combined with unpredictable maternal stress, whereby pups were separated from their mother at an unpredictable time during the light or dark cycle and during which time the mother was also exposed to a brief unpredictable stressor at an unpredictable time during the 3 h separation period. In agreement with our findings in socially defeated male GABABð1aÞ-=- mice, we found that maternally separated female GABABð1bÞ-=- mice also exhibited an anhedonic-like response in the saccharin preference test when compared with both GABABð1bÞ-=- and wild-type mice. We also assessed the effects of maternal separation on anhedonia in male mice using the female urine sniffing test (Malkesman et al., 2010). In this test, a cotton bud dipped in water or the urine of female mice that are in estrus is presented to the male mouse in its home cage. Male mice tend to spend more time sniffing the urine over water, and this is taken as a measure of sexual interest. It has been previously shown that rodents that exhibit learned helplessness spend less time sniffing the urine, an effect prevented by chronic antidepressant treatment (Malkesman et al., 2010). Maternal separation decreased the preference for urine in wild-type mice and completely abolished this preference in GABABð1aÞ-=- mice while having no effect in GABABð1bÞ-=- mice (O’Leary et al., 2014). Together with the findings from the social defeat experiment, this suggests that GABABð1aÞ-=- mice are more susceptible, whereas GABABð1bÞ-=- mice are more resilient to stress-induced anhedonia. The impact of chronic stress on antidepressant-like behavior was also assessed in these mice using the FST and tail suspension test, but the findings from these tests were more complex than those assessing anhedonia readouts. This was due in part to genotype differences under control conditions. Under baseline conditions, both GABABð1aÞ-=- and GABABð1bÞ-=- mice exhibited decreased immobility in the FST (O’Leary et al., 2014). Although these findings might be interpreted as both GABABð1aÞ-=- and GABABð1bÞ-=- mice having an antidepressant-like phenotype in the FST, a different picture emerges when they were exposed to maternal separation stress. In the FST we found that female (but not male) maternally separated GABABð1bÞ-=- mice retained their antidepressant-like behavioral phenotype suggesting they were more stress resilient, whereas maternally separated GABABð1aÞ-=- mice did not retain this phenotype. In addition, in the tail suspension test, both nonstressed and stressed male and female GABABð1aÞ-=- mice exhibited increased immobility, thus suggesting that GABABð1aÞ-=- mice have a depression-like behavioral phenotype in this test. On the other hand, both nonstressed and stressed male GABABð1bÞ-=- mice exhibited reduced immobility, thus suggesting an antidepressant-like phenotype. However, caution is required when interpreting these reductions in immobility in GABABð1bÞ-=- mice, as another study did not observe this decreased immobility in the FST (Jacobson et al., 2017), and these mice also show increased locomotor activity (O’Leary et al., 2014). Nevertheless, we also observed the female maternally separated GABABð1bÞ-=- mice do not exhibit hyperactivity and yet exhibit reduced immobility in the FST; thus a role in antidepressant-like behavior cannot be completely discounted.
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Although the data gathered from GABABð1aÞ-=- and GABABð1bÞ-=- mice suggest that deletion of either subunit isoform can differentially modulate stress resilience, surprisingly little work has been done on investigating whether the expression of these subunits is altered by stress or models of stress-related psychiatric disorders. Nevertheless, we have reported that the helpless H/Rouen genetic mouse model of depression exhibits increased GABAB(1b) mRNA expression in the hippocampus when compared with their nonhelpless controls (O’Leary et al., 2014) and that a probiotic that promotes antidepressant-like effects increased the expression of this subunit in the mouse hippocampus (Bravo et al., 2011). In contrast, we did not observe any changes in hippocampal GABAB1a mRNA expression in the helpless H/Rouen mouse strain (O’Leary et al., 2014). On the other hand, a previous small postmortem human brain study reported that GABAB1a mRNA expression was decreased in the dentate gyrus of depressed individuals (Ghose et al., 2011), and others have reported antidepressant-induced increases in GABAB1a mRNA expression in the rat hippocampus (Sands et al., 2004). Given these somewhat opposing findings, a more systematic investigation of brain-wide impact of depression, stress, and antidepressant treatments on the expression of these subunit isoforms is required. Taken together, these studies support a role for the GABAB1a receptor in depression, in antidepressant action, and in determining stress susceptibility, whereby reduced GABAB1a expression in the hippocampus is associated with depression in humans and increased stress susceptibility in mice, whereas increased hippocampal expression seems to occur following antidepressant treatment. On the other hand, increased GABAB1b expression in the hippocampus is a phenotype of a genetic mouse model of depression, and deletion of this subunit increases stress resilience in mice.
Potential mechanisms underlying the differential roles of GABAB1a and GABAB1b receptor subunit isoforms in stress resilience The neurobiological mechanisms underlying the differential roles of the GABAB1a and GABAB1b receptor subunit isoforms in stress resilience are not yet fully understood, but as outlined in the following sections, several studies suggest that the serotonin neurotransmitter system, the hypothalamic-pituitary-adrenal (HPA) axis, selected brain regions, and adult hippocampal neurogenesis may play a role.
The serotonin neurotransmitter system The serotonin (5-HT) neurotransmitter system has long been implicated in the pathophysiology and treatment of the stress-related psychiatric disorder depression (O’Leary and Cryan, 2010; Lucki, 1998). Indeed, the selective serotonin reuptake inhibitor (SSRI) antidepressants were developed to increase synaptic availability of this neurotransmitter in the brain. There is growing evidence of a functional link between the serotonin system and GABAB receptors. Indeed, most 5-HT cell bodies in the dorsal and medial raphe nuclei express the GABAB receptor (Abellan et al., 2000a; Varga et al., 2002). In addition, it has been demonstrated that activation of GABAB receptors by the agonist, baclofen, modulates the release of 5-HT in the DRN, the nucleus accumbens, and the striatum (Abellan et al.,
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2000a,b; Tao et al., 1996; Takahashi et al., 2010). Moreover, we have previously shown that the antidepressant-like effects of GABAB receptor antagonists in the rat-FST are dependent on an intact serotonergic system (Slattery et al., 2005). Reciprocally, mice lacking the serotonin transporter exhibit desensitized GABAB receptors in the raphe nuclei (la Cour et al., 2004), and rats chronically treated with the SSRI, fluoxetine, exhibit reduced GABAB receptoremediated GIRK responses in the DRN (Cornelisse et al., 2007). Importantly in the context of stress, it has been shown that social defeat stress increases GABA-mediated inhibition of 5-HT in the DRN of stress-susceptible mice, whereas GABA silencing disinhibited serotonergic cells and promoted a stress-resilient phenotype in mice exposed to social defeat (Challis et al., 2013). This suggests that GABA-serotonin interactions in the DRN play a role in stress resilience. Indeed, we have found that GABABð1bÞ-=- mice (which are more stress resilient) exhibit enhanced stress-induced expression of the immediate early gene, c-Fos, in the DRN, when compared with the stresssusceptible GABABð1aÞ-=- or the normo-stress-sensitive wild-type mice, thus suggesting that the DRN is a key brain region involved in GABAB1 receptor subunit regulation of stress resilience (O’Leary et al., 2014). The 5-HT1A receptor is thought to play a pivotal role in the stress-related psychiatric disorders, depression, and anxiety (O’Leary and Cryan, 2010; Blier and Ward, 2003; Cryan and Leonard, 2000). These receptors are localized in the raphe nuclei where they act as somatodendritic autoreceptors that inhibit 5-HT cell firing but are also found postsynaptically in a number of limbic brain regions important in the regulation of emotion, such as the hippocampus (Hoyer et al., 2002). Desensitization of this receptor has been long implicated in the mechanism of antidepressant action (Blier and Ward, 2003; Albert et al., 2014; Hensler, 2003; De Vry, 1995) and in enhancing the onset of antidepressant action perhaps through increased 5-HT availability in the forebrain (Artigas et al., 1996; Blier et al., 1997; Ferres-Coy et al., 2013). Thus, we recently examined 5-HT1a receptoremediated responses in both GABABð1aÞ-=- and GABABð1bÞ-=- mice (Jacobson et al., 2017). In this study, both male and female GABABð1aÞ-=- mice exhibited a blunted hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT, thus suggesting that these mice have impaired presynaptic 5-HT1A autoreceptor function (Jacobson et al., 2017). In agreement with these findings, previous in situ hybridization studies suggest that it is the GABAB1a isoform that is predominantly expressed on serotonergic cell bodies in the DRN (Bischoff et al., 1999). GABABð1aÞ-=- mice also exhibited attenuated 8-OH-DPAT-induced stimulation of the HPA axis and body posture flattening, thus suggesting that postsynaptic 5-HT1A receptors are also densensitized, although this desensitization seems to be weaker than that occurring at presynaptic 5-HT1A receptors (Jacobson et al., 2017). These effects were generally not associated with alterations in 5-HT1A receptor expression nor with alterations in 5-HT1a receptor G-protein coupling. In addition, no alterations in 8-OH-DPAT-induced responses were observed in the GABABð1bÞ-=- mice (Jacobson et al., 2017). Taken together, these data suggest that the DRN may be an important brain region involved in the stress-resilient phenotype of GABABð1bÞ-=- mice and that the sensitivity of presynaptic and postsynaptic 5-HT1A receptors is reduced in the stress-susceptible GABABð1aÞ-=- mice. Given the role of 5-HT1A receptor desensitization in the response to SSRI antidepressants, it will be of interest to determine whether GABABð1aÞ-=- mice exhibit altered sensitivity to these drugs.
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The hypothalamic-pituitary-adrenal axis Because the HPA axis is strongly implicated in stress resilience and vulnerability (Franklin et al., 2012; Reul et al., 2015; Henckens et al., 2016), it comes as no surprise that its function has been somewhat interrogated in GABAB1 subunit isoform knockout mice (O’Leary et al., 2014; Jacobson et al., 2017). Under baseline conditions, plasma corticosterone concentrations do not seem to differ between wild-type, GABABð1aÞ-=- , and GABABð1bÞ-=- male mice (Jacobson et al., 2017). However, GABABð1aÞ-=- mice exhibit blunted corticosterone and adrenocorticotropic hormone (ACTH) release in response to the 5-HT1A receptor agonist 8-OH-DPAT, whereas GABABð1bÞ-=- mice did not differ from wild-type mice (Jacobson et al., 2017). This suggests that serotonergic regulation of the HPA axis is impaired in GABABð1aÞ-=- mice. We have also examined the impact of stress on plasma corticosterone in GABABð1bÞ-=- and GABABð1bÞ-=- mice. In male mice, stress-induced increases in plasma corticosterone were decreased in GABABð1aÞ-=- mice and increased in GABABð1bÞ-=mice (O’Leary et al., 2014). However, these differences in stress-induced corticosterone concentrations cannot fully explain the differential susceptibility of GABABð1aÞ-=- and GABABð1bÞ-=- mice to stress-induced changes in behavior. This is because female GABABð1aÞ-=- and GABABð1bÞ-=- mice did not differ in their corticosterone response to stress but yet exhibited differential susceptibility to stress-induced changes in depression-like behavior (O’Leary et al., 2014). However, it must also be kept in mind that there is sexual dimorphism in HPA axis regulation, and thus, it is unlikely that stress-induced changes in this system and its contribution to stress resilience would be similar in both males and females (Goel et al., 2014; Bangasser and Valentino, 2012).
Location, location, location. Toward identifying the neural circuitry underlying the differential stress susceptibility between GABABð1aÞ-=- and GABABð1bÞ-=- mice, we measured the effects of acute restraint stress on the expression of c-Fos (an immediate early gene) in several stress-related brain areas in adult wild-type, GABABð1aÞ-=-, and GABABð1bÞ-=- mice, with and without prior maternal separation stress. The nucleus accumbens was the only area where stress-induced c-Fos expression was differentially regulated in the stress-resilient GABABð1bÞ-=- mice by prior exposure to maternal separation stress. Specifically, maternal separation significantly increased stressinduced c-Fos expression in the nucleus accumbens of GABABð1bÞ-=- mice but not in wildtype or GABABð1aÞ-=- mice, and these effects of acute stress were not apparent in GABABð1bÞ-=- mice that had not undergone prior maternal separation. This suggests that the nucleus accumbens may be a key node in the neural circuitry of stress resilience in GABABð1bÞ-=- mice. Interestingly, GABABð1aÞ-=- mice exhibited decreased stress-induced cFos activation in the ventral tegmental area (VTA), and this effect was not apparent in GABABð1aÞ-=- mice that had undergone maternal separation, thus suggesting that the VTA might play a role in the stress-susceptible phenotype of these mice. Indeed, dysfunction of the nucleus accumbens and its associated reward circuitry including the VTA has already been implicated in susceptibility to stress-induced anhedonia (Russo and Nestler, 2013). Moreover, it is well established that GABAB receptors modulate VTA and nucleus
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accumbensemediated hedonic processing as systemic, intra-VTA, or intranucleus accumbens (shell) administration of GABAB receptor agonists attenuates the rewarding effects of several drugs of abuse (Vlachou and Markou, 2010). Although there is clear role for GABAB receptor modulation of the hedonic effects of drugs of abuse, relatively little is known about GABAB receptor modulation of stress-induced anhedonia. Nevertheless, one study reported that reductions in sucrose preference induced by chronic mild stress in rats were prevented by chronic treatment with a GABAB receptor antagonist (Nowak et al., 2006), and we have shown that GABABð1aÞ-=- mice are more susceptible, whereas GABABð1bÞ-=- mice are more resilient to stress-induced anhedonia (O’Leary et al., 2014). Taken together, stress-induced differential neuronal activity patterns in the VTAnucleus accumbens reward system of the brain in GABABð1bÞ-=- and GABABð1aÞ-=- mice may at least partially contribute their differential susceptibility to stress-induced anhedonia although this has yet to be directly tested by inhibiting these isoforms specifically in the nucleus accumbens or VTA. One of the most robust genotype-dependent effects of acute stress on c-Fos expression was observed in the hippocampus (O’Leary et al., 2014), a key brain area involved in regulation of the stress response (Jacobson and Sapolsky, 1991; Brown et al., 1999) whereby the number of cFos-positive cells in response to acute stress was significantly increased in GABABð1bÞ-=- mice compared with wild-type and GABABð1aÞ-=- mice. This enhanced stress-induced c-Fos activation was most apparent in the dentate gyrus and ventral CA3 regions of the hippocampus and occurred to the same extent in both nonseparated and maternally separated GABABð1bÞ-=- mice. Interestingly, GABABð1aÞ-=- mice exhibited decreased stress-induced c-Fos in the ventral CA3, and this effect was not apparent when they had undergone prior maternal separation. Together, this suggests that GABAB receptors in the hippocampus might be important in the differential response to stress, and this observation is further supported by our findings (described in the next section) that maternal separation stress differentially affects adult hippocampal neurogenesis in GABABð1bÞ-=- versus GABABð1aÞ-=- mice. Finally, we also observed that GABABð1bÞ-=- mice exhibited enhanced stress-induced neural activation in the DRN irrespective of whether they had undergone prior maternal separation or not, but unlike the hippocampus, these increases were largely restricted to comparisons with GABABð1aÞ-=- and not wild-type mice (O’Leary et al., 2014). As described earlier in this chapter, there is accumulating evidence of a GABAB-serotonin interactions in the DRN (Cornelisse et al., 2007; Slattery et al., 2005; Takahashi et al., 2010), and the DRN plays a role in stress resilience (Challis et al., 2013). Taken together, this supports the hypothesis that GABAB receptors in the DRN may play a role in stress resilience. Within this context, however, it is noteworthy that it is the GABAB1a isoform rather than the GABAB1b isoform that is mainly expressed on serotonergic cells bodies DRN (Bischoff et al., 1999) and yet we did not observe any differences in stress-induced c-FOS expression in GABABð1aÞ-=- mice when compared with wild-type mice.
Adult hippocampal neurogenesis: a mechanism for resilience? Neurogenesis, the birth of new neurons, occurs in just a few areas of the adult brain including the dentate gyrus of the hippocampus, and several extrinsic factors can alter the
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proliferation and survival of these adult-born neurons including stress and chronic antidepressant treatments (Kempermann et al., 2015; Bergmann et al., 2015; Christian et al., 2014; Malberg et al., 2000; O’Leary et al., 2013). Moreover, there is emerging evidence that these adult-born hippocampal neurons may play a role in buffering the stress response as well as antidepressant regulation of the HPA axis (Levone et al., 2015; Snyder et al., 2011; Surget et al., 2011). Accumulating evidence suggests that the GABAB receptor also modulates adult hippocampal neurogenesis (Felice et al., 2012; O’Leary et al., 2014; Giachino et al., 2014). GABAB1-=- mice exhibit increased adult hippocampal progenitor cell proliferation as well as accelerated neuronal differentiation when compared with their wild-type counterparts (Giachino et al., 2014). In addition, we have shown that a GABAB receptor antagonist, CGP52432, which has antidepressant-like behavioral effects in the FST increased hippocampal cell proliferation in mice (Felice et al., 2012). Interestingly, we observed that the effect of CGP52432 on hippocampal cell proliferation occurred in the ventral rather than the dorsal hippocampus. This finding is intriguing in light of a growing body of evidence that suggests the hippocampus is functionally segregated along its longitudinal axis into dorsal and ventral regions, whereby the dorsal hippocampus (dHi) plays a predominant role in the spatial learning and memory, whereas the ventral hippocampus (vHi) plays a predominant role in the regulation of emotion-related processes (Bannerman et al., 2004; Fanselow and Dong, 2010). Moreover, there is emerging evidence that adult neurogenesis may also be differentially regulated along this axis with the effects of stress on neurogenesis occurring predominantly in the vHi (Tanti and Belzung, 2013; O’Leary and Cryan, 2014; O’Leary et al., 2012). Given the impact of stress and the GABAB receptor on adult hippocampal neurogenesis, and the identification of the hippocampus as a key brain area expressing altered neuronal responses to stress (as measured by c-Fos expression) in GABABð1bÞ-=- versus GABABð1aÞ-=mice, we examined whether increased adult hippocampal neurogenesis may contribute to the stress-resilient phenotype of the GABABð1bÞ-=- mice (O’Leary et al., 2014). We found that male GABABð1bÞ-=- mice exhibit increased proliferation of newly born cells in the vHi but not dHi. We also found that these stress-resilient GABABð1bÞ-=- mice exhibited increased survival of new adult-born cells in the hippocampus. Interestingly, we found that under baseline conditions, this increase in the survival of new adult-born cells occurred in the dHi but not the vHi, but in GABABð1bÞ-=- mice that had undergone early-life stress (maternal separation), this increased survival of new adult-born cells shifted from the dorsal to the ventral hippocampus. Thus, further supporting the emerging view that adult neurogenesis in the vHi rather than the dHi plays a predominant role in the response to stress. GABABð1bÞ-=- mice were also resistant to the early-life stress-induced decrease in the survival of adult-born cells in the vHi, thus suggesting a possible mechanism underlying their stress-resilient behavioral phenotype. Using female mice, we confirmed that increased adult hippocampal neurogenesis occurs in GABABð1bÞ-=- mice, whereas no differences were observed between GABABð1aÞ-=mice and wild-type mice. This finding also suggests that the increases in adult hippocampal neurogenesis observed in GABABð1bÞ-=- mice is not sex dependent and thus parallels the sex-independent stress-resilient behavioral phenotype observed in these mice (O’Leary et al., 2014).
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The mechanisms underlying GABAB receptor modulation of adult hippocampal neurogenesis are not yet known but may involve regulation of brain-derived neurotrophic factor (BDNF). BDNF is a neurotrophin involved in adult hippocampal neurogenesis. Moreover, it is required for antidepressant-induced increases in adult hippocampal neurogenesis and antidepressant-like behavior, and it also plays a role in stress resilience (O’Leary and Castren, 2010; Sairanen et al., 2005; Saarelainen et al., 2003; Berton et al., 2006; Krishnan et al., 2007; Bjorkholm and Monteggia, 2016). GABAB receptor antagonists have been shown to elevate BDNF protein and mRNA levels in various brain regions including the hippocampus (Heese et al., 2000; Enna et al., 2006). Thus, it will be of interest to determine whether the stress-resilient phenotypes of GABABð1bÞ-=- are due to enhanced BDNF signaling.
Conclusions In summary, GABAB1 receptor subunit isoforms differentially regulate stress resilience (Fig. 5.1). Reductions or deletions of GABAB1b are associated with an antidepressant-like behavioral phenotype and resilience to psychostress-induced anhedonia and psychosocial stress-induced social avoidance, whereas increased hippocampal GABAB1b expression in the hippocampus has been found in a genetic mouse model of depression. On the other hand, mice lacking the GABAB1a receptor subunit isoform are more susceptible to stressinduced anhedonia and social avoidance. Experiments using c-Fos immunohistochemistry to delineate the neural circuitry underlying the differential stress sensitivity of GABABð1bÞ-=and GABABð1aÞ-=- mice suggest that the VTA-nucleus accumbens reward pathway, the DRN, and the hippocampus are likely key brain areas involved in this neural circuitry. Moreover, adult hippocampal neurogenesis and the serotonin neurotransmitter system have been shown to be differentially affected in GABABð1aÞ-=- and GABABð1bÞ-=- mice. Taken together, the GABAB1a and GABAB1b subunit isoforms represent potential novel therapeutic targets for the treatment of stress-related psychiatric disorders.
Acknowledgements We thank Dr. Daniela Felice for assistance in creating Fig. 5.1.
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5 GABAB receptors, depression, and stress resilience: a tale of two isoforms Olivia F. O’Leary1, 2, John F. Cryan1, 2 1
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; 2APC Microbiome Institute, University College Cork, Cork, Ireland
Introduction In the central nervous system, gamma-aminobutyric acid (GABA) acts on two types of receptors: ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors. GABAA receptors are ligand-gated ion channels while GABAB receptors are G-protein-coupled receptors. GABAB receptors are found presynaptically where they function as either autoreceptors limiting the release of GABA or as heteroreceptors inhibiting the release of glutamate. However, these receptors are also found postsynaptically where they induce slow inhibitory postsynaptic currents (Cryan and Kaupmann, 2005; Bettler et al., 2004). Functional GABAB receptors are heterodimers of GABAB1 and GABAB2 subunits, and the GABAB1 subunit is expressed as several isoforms (Lee et al., 2010; Fritschy et al., 1999). The GABAB1a and GABAB1b isoforms are the predominant subunit isoforms that are expressed in the brain, whereby the GABAB1b subunit isoform is predominantly localized postsynaptically, whereas the GABAB1a subunit isoform is mainly found presynaptically (Fritschy et al., 1999; Gassmann and Bettler, 2012; Vigot et al., 2006). In dendrites, GABAB1a localizes to glutamatergic terminals for heteroreceptor function, whereas GABAB1b localizes to spines opposing glutamate release sites, thus affecting presynaptic or postsynaptic inhibition (Gassmann and Bettler, 2012). Structurally, these two isoforms differ only by the presence of a sushi domain in the N-terminus of the GABAB1a receptor subunit isoform, which is thought to increase surface stability of GABAB(1a, 2) receptors and promote their axonal localization (Gassmann and Bettler, 2012; Hannan et al., 2012). Interest in the role of the GABAB receptor in stress resilience began 30 years ago, when a potential role for the GABAB receptor in the pathophysiology and treatment of the Stress Resilience https://doi.org/10.1016/B978-0-12-813983-7.00005-7
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stress-related disorder, depression, was first reported (Pilc and Lloyd, 1984). Since then, many preclinical studies have reported a reciprocal but complex relationship between stress-related psychiatric disorders such as depression and anxiety with the GABAB receptor as outlined in the following sections.
The impact of stress-related psychiatric disorders and their treatments on GABAB receptor density, gene expression and function Effects of antidepressants on GABAB receptor density in rodents The first hint that the GABAB receptor may play a role in stress-related responses came from receptor binding studies in the early 1980s, which examined the effects of antidepressant treatments on GABAB receptor density (Pilc and Lloyd, 1984). Since then, many other studies have reported that this receptor is affected by several different antidepressant treatments although some conflicting and brain region-dependent results have also been reported (Felice et al., 2016; Ghose et al., 2011; Cryan and Slattery, 2010; Enna and Bowery, 2004). It was reported that chronic but not acute treatment with the antidepressants amitriptyline, desipramine, or citalopram increased GABAB receptor-binding sites (i.e., receptor density) in the rat frontal cortex (Pilc and Lloyd, 1984). These findings were reproduced in a later study, which also reported that other antidepressant treatments including fluoxetine, mianserin, trazodone, and repeated electroconvulsive shocks upregulated GABAB receptor binding in the rat frontal cortex (Lloyd et al., 1985). Such effects of antidepressants on GABAB receptor binding seemed to be region dependent and were not apparent in the rat hippocampus (Lloyd et al., 1985). Chronic treatment with the antidepressant imipramine was also shown to increase GABAB receptor binding in the mouse cortex (Suzdak and Gianutsos, 1986). However, opposing data have also been reported. For instance, Pratt and Bowery (1993) reported that although desipramine increased GABAB receptor binding in the rat frontal cortex, neither paroxetine nor amitriptyline had any effect (Pratt and Bowery, 1993). Similarly, a lack of effect of desipramine, imipramine, and tranylcypromine on frontal cortex GABAB receptor binding has been reported by others (Cross and Horton, 1987, 1988; McManus and Greenshaw, 1991). On the other hand, the antidepressants desipramine and imipramine have been shown to reverse the reduction in frontal cortex GABAB receptor that is induced by learned helplessness, thus suggesting that antidepressants may affect GABAB receptor density not only under basal conditions but also in depression-like states (Martin et al., 1989).
Effects of antidepressants on GABAB receptor function in rodents These findings of antidepressant-induced increases in GABAB receptor density in the cortex are consistent with findings that GABAB receptor function is increased following various antidepressant treatments. Indeed, it has been reported that imipramine-induced increases in GABAB receptor density were accompanied by enhanced receptor function as shown by the potentiation of baclofen (a GABAB receptor agonist)-induced adenylate cyclase activity in the mouse cerebral cortex (Suzdak and Gianutsos, 1986).
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Repeated treatment with the antidepressant tranylcypromine has also been reported to enhance GABAB receptor function in the rat cerebral cortex as measured by baclofenstimulated GTPgS binding (Sands et al., 2003). Similarly, chronic treatment with amitriptyline, desipramine, mianserin, or electroconvulsive shock increased GABAB receptoremediated modulation of serotonin release in the mouse frontal cortex (Gray and Green, 1987). In contrast to all of these findings, however, one study reported that antidepressants including desipramine and imipramine do not alter GABAB receptor function in the cerebral cortex (Szekely et al., 1987). Interestingly, 7 days treatment with the antidepressants tranylcypromine, phenelzine, or desipramine (but not fluoxetine) increased GABAB receptor function in the rat hippocampus (Sands et al., 2004). This suggests that although antidepressants affect GABAB receptor density in the frontal cortex but not hippocampus (Lloyd et al., 1985), these drugs can affect receptor function in both the hippocampus and the frontal cortex (Lloyd et al., 1985; Sands et al., 2004). However, it should also be noted that the direction of change of antidepressant effects on GABAB receptor function may be region dependent, as it has been reported that chronic fluoxetine treatment reduced GABAB receptoreinduced GIRK responses in the rat dorsal raphe nucleus (DRN) (Cornelisse et al., 2007).
Clinical evidence of altered GABAB receptor density and function in depression and the antidepressant response All of this preclinical evidence is supported by a growing body of clinical evidence of GABAB receptor dysfunction in depression (for review, see Felice et al., 2016; Ghose et al., 2011). Indeed, recent clinical neurophysiology studies suggest that deficits in GABAB receptors may play a role in major depression and the antidepressant response to fluoxetine (Levinson et al., 2010; Croarkin et al., 2014). In addition, the induction of growth hormone release by the GABAB receptor agonist baclofen is blunted in depressed patients (O’Flynn and Dinan, 1993; Marchesi et al., 1991). Moreover, it has been reported that the GABAB2 receptor subunit is upregulated in cortical and subcortical brain regions in depressed suicide victims compared with those without a history of depression (Klempan et al., 2009). Similarly, a 50% increase in GABAB2 subunit gene expression was reported in the dentate gyrus of the hippocampus in depressed individuals (Ghose et al., 2011). However, this upregulation is not reflected in earlier receptor binding studies in which similar GABAB receptorebinding profiles in the frontal or temporal cortices and the hippocampus had been reported in depressed suicide victims and controls (Cross et al., 1988) and in the frontal cortex of suicide victims and controls (Arranz et al., 1992).
Alterations in GABAB receptor density and function in animal models of stress and depression Considering the relatively strong evidence for a potential role of the GABAB receptor in depression and the response to antidepressants, it is somewhat surprising that only a limited number of preclinical studies have measured GABAB receptor expression and
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function in animal models of depression and stress. It has been reported that GABAB receptor binding in the frontal cortex is reduced in the rat learned helplessness model of depression (Martin et al., 1989). On the other hand, however, chronic restraint stress (7 days) had no effect on GABAB receptor activity in the cerebral cortex as measured by baclofen-stimulated GTPgS binding (Sands et al., 2003). Similarly, social stress did not affect GABAB receptoremediated GIRK currents in the rat DRN (Cornelisse et al., 2007). In summary, most preclinical studies have reported that chronic treatment with several different antidepressants increases GABAB receptor density and activity particularly in the cortex. In support, clinical studies suggest that deficits in GABAB receptor function may play a role in major depression and the antidepressant response to fluoxetine; however, only a limited number of clinical studies have actually been conducted. Although no differences in GABAB receptorebinding profiles have been reported in the frontal and temporal cortices of the suicide brain, increased expression of the GABAB2 receptor subunit has been reported in the hippocampus and cortex of depressed suicide victims. Taken together, these preclinical and clinical studies on GABAB receptor density and activity suggest a role for the GABAB receptor in antidepressant action and perhaps a more indirect or limited role in the pathophysiology of stress and depression. Nevertheless, as outlined in the following sections, it is clear that altering GABAB receptor activity regulates depression and anxietylike behaviors and behavioral responses to stress.
Effects of GABAB receptor modulation on depression-like behaviors There is a large body of convincing preclinical evidence that pharmacological or genetic manipulation of the GABAB receptor affects anxiety-, depression-, and antidepressantrelated behaviors (Cryan and Kaupmann, 2005; Felice et al., 2016; Cryan and Slattery, 2010). Mice with null mutations of either the GABAB1 or GABAB2 receptor subunits demonstrate an antidepressant-like behavioral phenotype as indicated by reduced immobility in the forced swim test (FST; Mombereau et al., 2004, 2005). Moreover, GABAB receptor antagonists exert antidepressant-like effects in the FST, and in the learned helplessness, olfactory bulbectomy, and chronic mild stress paradigms (reviewed in Felice et al., (2016)). Specifically, the GABAB receptor antagonists CGP56433A, CGP51176, CGP5633A, CGP36742, and SCH50911 have all been shown to induce antidepressant-like behavior in the FST in rats or mice (Mombereau et al., 2004; Slattery et al., 2005; Nowak et al., 2006; Frankowska et al., 2007; Felice et al., 2012). GABAB receptor antagonists are also effective in other rodent models of depression and antidepressant activity including the olfactory bulbectomy model (CGP36742 and CGP51176) (Nowak et al., 2006), chronic mild stress (CGP51176) (Nowak et al., 2006), and learned helplessness model (CGP36742) (Nakagawa et al., 1999). On the other hand, it is positive allosteric modulators (PAMs) of GABAB receptors that exert anxiolytic effects in tests of innate anxiety although PAMs do not exert any effects in conditioned fear paradigms (Frankowska et al., 2007; Sweeney et al., 2013; Li et al., 2015; Cryan et al., 2004). Taken together, it is clear that reducing GABAB receptor function has antidepressant-like effects, whereas positive allosteric modulation of the receptor has anxiolytic effects.
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The role of GABAB1 receptor subunit isoforms in stress resilience Although it is clear that pharmacological modulation of GABAB receptors can influence depression and anxiety-like behaviors, relatively few studies have examined their effects in the behavioral responses to chronic stress. Nevertheless, it has been reported that the GABAB receptor antagonist, CGP51176, prevented anhedonia in the chronic mild stress paradigm (Nowak et al., 2006). More recently, we have used GABABð1aÞ-=- and GABABð1bÞ-=- mice as tools to delineate the roles of specific GABAB1 receptor subunit isoforms in depression and anxiety-related behaviors as well as in resilience and susceptibility to stress-induced changes in these behaviors. Indeed, we recently reported that GABAB1a and GABAB1b receptor subunit isoforms differentially regulate stress resilience in both male and female mice (O’Leary et al., 2014) (Fig. 5.1). Specifically, male GABABð1aÞ-=- mice were more susceptible, whereas male GABABð1bÞ-=- mice were more resilient to chronic social defeat stress (O’Leary et al., 2014). In the social interaction test, social defeat stress decreased social interaction to a greater extent in GABABð1aÞ-=- mice when compared with wild-type mice. On the other hand, mice lacking the GABABð1bÞ-=- isoform were resilient to this stress-induced social avoidance. Moreover,
FIGURE 5.1 Summary of the main differences between GABABð1aÞ-=- mice in their response to stress and potential underlying mechanisms of stress resilience in GABABð1bÞ-=- mice. CORT, corticosterone; DRN, dorsal raphe nucleus; FST, forced swim test; MS, maternal separation; NAcc, nucleus accumbens; SDS, social defeat stress; TST, tail suspension test.
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social defeat stress induced anhedonia in GABABð1aÞ-=- mice as measured by reduced preference to drink a sweet solution of saccharin over water, whereas GABABð1bÞ-=- mice were resilient to this measure of stress-induced anhedonia. In an independent cohort of mice, we also examined the impact of early-life stress on depression and anxiety-related behaviors in adulthood and using a model amenable to both male and female mice (O’Leary et al., 2014). To this end, we used unpredictable maternal separation combined with unpredictable maternal stress, whereby pups were separated from their mother at an unpredictable time during the light or dark cycle and during which time the mother was also exposed to a brief unpredictable stressor at an unpredictable time during the 3 h separation period. In agreement with our findings in socially defeated male GABABð1aÞ-=- mice, we found that maternally separated female GABABð1bÞ-=- mice also exhibited an anhedonic-like response in the saccharin preference test when compared with both GABABð1bÞ-=- and wild-type mice. We also assessed the effects of maternal separation on anhedonia in male mice using the female urine sniffing test (Malkesman et al., 2010). In this test, a cotton bud dipped in water or the urine of female mice that are in estrus is presented to the male mouse in its home cage. Male mice tend to spend more time sniffing the urine over water, and this is taken as a measure of sexual interest. It has been previously shown that rodents that exhibit learned helplessness spend less time sniffing the urine, an effect prevented by chronic antidepressant treatment (Malkesman et al., 2010). Maternal separation decreased the preference for urine in wild-type mice and completely abolished this preference in GABABð1aÞ-=- mice while having no effect in GABABð1bÞ-=- mice (O’Leary et al., 2014). Together with the findings from the social defeat experiment, this suggests that GABABð1aÞ-=- mice are more susceptible, whereas GABABð1bÞ-=- mice are more resilient to stress-induced anhedonia. The impact of chronic stress on antidepressant-like behavior was also assessed in these mice using the FST and tail suspension test, but the findings from these tests were more complex than those assessing anhedonia readouts. This was due in part to genotype differences under control conditions. Under baseline conditions, both GABABð1aÞ-=- and GABABð1bÞ-=- mice exhibited decreased immobility in the FST (O’Leary et al., 2014). Although these findings might be interpreted as both GABABð1aÞ-=- and GABABð1bÞ-=- mice having an antidepressant-like phenotype in the FST, a different picture emerges when they were exposed to maternal separation stress. In the FST we found that female (but not male) maternally separated GABABð1bÞ-=- mice retained their antidepressant-like behavioral phenotype suggesting they were more stress resilient, whereas maternally separated GABABð1aÞ-=- mice did not retain this phenotype. In addition, in the tail suspension test, both nonstressed and stressed male and female GABABð1aÞ-=- mice exhibited increased immobility, thus suggesting that GABABð1aÞ-=- mice have a depression-like behavioral phenotype in this test. On the other hand, both nonstressed and stressed male GABABð1bÞ-=- mice exhibited reduced immobility, thus suggesting an antidepressant-like phenotype. However, caution is required when interpreting these reductions in immobility in GABABð1bÞ-=- mice, as another study did not observe this decreased immobility in the FST (Jacobson et al., 2017), and these mice also show increased locomotor activity (O’Leary et al., 2014). Nevertheless, we also observed the female maternally separated GABABð1bÞ-=- mice do not exhibit hyperactivity and yet exhibit reduced immobility in the FST; thus a role in antidepressant-like behavior cannot be completely discounted.
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Although the data gathered from GABABð1aÞ-=- and GABABð1bÞ-=- mice suggest that deletion of either subunit isoform can differentially modulate stress resilience, surprisingly little work has been done on investigating whether the expression of these subunits is altered by stress or models of stress-related psychiatric disorders. Nevertheless, we have reported that the helpless H/Rouen genetic mouse model of depression exhibits increased GABAB(1b) mRNA expression in the hippocampus when compared with their nonhelpless controls (O’Leary et al., 2014) and that a probiotic that promotes antidepressant-like effects increased the expression of this subunit in the mouse hippocampus (Bravo et al., 2011). In contrast, we did not observe any changes in hippocampal GABAB1a mRNA expression in the helpless H/Rouen mouse strain (O’Leary et al., 2014). On the other hand, a previous small postmortem human brain study reported that GABAB1a mRNA expression was decreased in the dentate gyrus of depressed individuals (Ghose et al., 2011), and others have reported antidepressant-induced increases in GABAB1a mRNA expression in the rat hippocampus (Sands et al., 2004). Given these somewhat opposing findings, a more systematic investigation of brain-wide impact of depression, stress, and antidepressant treatments on the expression of these subunit isoforms is required. Taken together, these studies support a role for the GABAB1a receptor in depression, in antidepressant action, and in determining stress susceptibility, whereby reduced GABAB1a expression in the hippocampus is associated with depression in humans and increased stress susceptibility in mice, whereas increased hippocampal expression seems to occur following antidepressant treatment. On the other hand, increased GABAB1b expression in the hippocampus is a phenotype of a genetic mouse model of depression, and deletion of this subunit increases stress resilience in mice.
Potential mechanisms underlying the differential roles of GABAB1a and GABAB1b receptor subunit isoforms in stress resilience The neurobiological mechanisms underlying the differential roles of the GABAB1a and GABAB1b receptor subunit isoforms in stress resilience are not yet fully understood, but as outlined in the following sections, several studies suggest that the serotonin neurotransmitter system, the hypothalamic-pituitary-adrenal (HPA) axis, selected brain regions, and adult hippocampal neurogenesis may play a role.
The serotonin neurotransmitter system The serotonin (5-HT) neurotransmitter system has long been implicated in the pathophysiology and treatment of the stress-related psychiatric disorder depression (O’Leary and Cryan, 2010; Lucki, 1998). Indeed, the selective serotonin reuptake inhibitor (SSRI) antidepressants were developed to increase synaptic availability of this neurotransmitter in the brain. There is growing evidence of a functional link between the serotonin system and GABAB receptors. Indeed, most 5-HT cell bodies in the dorsal and medial raphe nuclei express the GABAB receptor (Abellan et al., 2000a; Varga et al., 2002). In addition, it has been demonstrated that activation of GABAB receptors by the agonist, baclofen, modulates the release of 5-HT in the DRN, the nucleus accumbens, and the striatum (Abellan et al.,
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2000a,b; Tao et al., 1996; Takahashi et al., 2010). Moreover, we have previously shown that the antidepressant-like effects of GABAB receptor antagonists in the rat-FST are dependent on an intact serotonergic system (Slattery et al., 2005). Reciprocally, mice lacking the serotonin transporter exhibit desensitized GABAB receptors in the raphe nuclei (la Cour et al., 2004), and rats chronically treated with the SSRI, fluoxetine, exhibit reduced GABAB receptoremediated GIRK responses in the DRN (Cornelisse et al., 2007). Importantly in the context of stress, it has been shown that social defeat stress increases GABA-mediated inhibition of 5-HT in the DRN of stress-susceptible mice, whereas GABA silencing disinhibited serotonergic cells and promoted a stress-resilient phenotype in mice exposed to social defeat (Challis et al., 2013). This suggests that GABA-serotonin interactions in the DRN play a role in stress resilience. Indeed, we have found that GABABð1bÞ-=- mice (which are more stress resilient) exhibit enhanced stress-induced expression of the immediate early gene, c-Fos, in the DRN, when compared with the stresssusceptible GABABð1aÞ-=- or the normo-stress-sensitive wild-type mice, thus suggesting that the DRN is a key brain region involved in GABAB1 receptor subunit regulation of stress resilience (O’Leary et al., 2014). The 5-HT1A receptor is thought to play a pivotal role in the stress-related psychiatric disorders, depression, and anxiety (O’Leary and Cryan, 2010; Blier and Ward, 2003; Cryan and Leonard, 2000). These receptors are localized in the raphe nuclei where they act as somatodendritic autoreceptors that inhibit 5-HT cell firing but are also found postsynaptically in a number of limbic brain regions important in the regulation of emotion, such as the hippocampus (Hoyer et al., 2002). Desensitization of this receptor has been long implicated in the mechanism of antidepressant action (Blier and Ward, 2003; Albert et al., 2014; Hensler, 2003; De Vry, 1995) and in enhancing the onset of antidepressant action perhaps through increased 5-HT availability in the forebrain (Artigas et al., 1996; Blier et al., 1997; Ferres-Coy et al., 2013). Thus, we recently examined 5-HT1a receptoremediated responses in both GABABð1aÞ-=- and GABABð1bÞ-=- mice (Jacobson et al., 2017). In this study, both male and female GABABð1aÞ-=- mice exhibited a blunted hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT, thus suggesting that these mice have impaired presynaptic 5-HT1A autoreceptor function (Jacobson et al., 2017). In agreement with these findings, previous in situ hybridization studies suggest that it is the GABAB1a isoform that is predominantly expressed on serotonergic cell bodies in the DRN (Bischoff et al., 1999). GABABð1aÞ-=- mice also exhibited attenuated 8-OH-DPAT-induced stimulation of the HPA axis and body posture flattening, thus suggesting that postsynaptic 5-HT1A receptors are also densensitized, although this desensitization seems to be weaker than that occurring at presynaptic 5-HT1A receptors (Jacobson et al., 2017). These effects were generally not associated with alterations in 5-HT1A receptor expression nor with alterations in 5-HT1a receptor G-protein coupling. In addition, no alterations in 8-OH-DPAT-induced responses were observed in the GABABð1bÞ-=- mice (Jacobson et al., 2017). Taken together, these data suggest that the DRN may be an important brain region involved in the stress-resilient phenotype of GABABð1bÞ-=- mice and that the sensitivity of presynaptic and postsynaptic 5-HT1A receptors is reduced in the stress-susceptible GABABð1aÞ-=- mice. Given the role of 5-HT1A receptor desensitization in the response to SSRI antidepressants, it will be of interest to determine whether GABABð1aÞ-=- mice exhibit altered sensitivity to these drugs.
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The hypothalamic-pituitary-adrenal axis Because the HPA axis is strongly implicated in stress resilience and vulnerability (Franklin et al., 2012; Reul et al., 2015; Henckens et al., 2016), it comes as no surprise that its function has been somewhat interrogated in GABAB1 subunit isoform knockout mice (O’Leary et al., 2014; Jacobson et al., 2017). Under baseline conditions, plasma corticosterone concentrations do not seem to differ between wild-type, GABABð1aÞ-=- , and GABABð1bÞ-=- male mice (Jacobson et al., 2017). However, GABABð1aÞ-=- mice exhibit blunted corticosterone and adrenocorticotropic hormone (ACTH) release in response to the 5-HT1A receptor agonist 8-OH-DPAT, whereas GABABð1bÞ-=- mice did not differ from wild-type mice (Jacobson et al., 2017). This suggests that serotonergic regulation of the HPA axis is impaired in GABABð1aÞ-=- mice. We have also examined the impact of stress on plasma corticosterone in GABABð1bÞ-=- and GABABð1bÞ-=- mice. In male mice, stress-induced increases in plasma corticosterone were decreased in GABABð1aÞ-=- mice and increased in GABABð1bÞ-=mice (O’Leary et al., 2014). However, these differences in stress-induced corticosterone concentrations cannot fully explain the differential susceptibility of GABABð1aÞ-=- and GABABð1bÞ-=- mice to stress-induced changes in behavior. This is because female GABABð1aÞ-=- and GABABð1bÞ-=- mice did not differ in their corticosterone response to stress but yet exhibited differential susceptibility to stress-induced changes in depression-like behavior (O’Leary et al., 2014). However, it must also be kept in mind that there is sexual dimorphism in HPA axis regulation, and thus, it is unlikely that stress-induced changes in this system and its contribution to stress resilience would be similar in both males and females (Goel et al., 2014; Bangasser and Valentino, 2012).
Location, location, location. Toward identifying the neural circuitry underlying the differential stress susceptibility between GABABð1aÞ-=- and GABABð1bÞ-=- mice, we measured the effects of acute restraint stress on the expression of c-Fos (an immediate early gene) in several stress-related brain areas in adult wild-type, GABABð1aÞ-=-, and GABABð1bÞ-=- mice, with and without prior maternal separation stress. The nucleus accumbens was the only area where stress-induced c-Fos expression was differentially regulated in the stress-resilient GABABð1bÞ-=- mice by prior exposure to maternal separation stress. Specifically, maternal separation significantly increased stressinduced c-Fos expression in the nucleus accumbens of GABABð1bÞ-=- mice but not in wildtype or GABABð1aÞ-=- mice, and these effects of acute stress were not apparent in GABABð1bÞ-=- mice that had not undergone prior maternal separation. This suggests that the nucleus accumbens may be a key node in the neural circuitry of stress resilience in GABABð1bÞ-=- mice. Interestingly, GABABð1aÞ-=- mice exhibited decreased stress-induced cFos activation in the ventral tegmental area (VTA), and this effect was not apparent in GABABð1aÞ-=- mice that had undergone maternal separation, thus suggesting that the VTA might play a role in the stress-susceptible phenotype of these mice. Indeed, dysfunction of the nucleus accumbens and its associated reward circuitry including the VTA has already been implicated in susceptibility to stress-induced anhedonia (Russo and Nestler, 2013). Moreover, it is well established that GABAB receptors modulate VTA and nucleus
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accumbensemediated hedonic processing as systemic, intra-VTA, or intranucleus accumbens (shell) administration of GABAB receptor agonists attenuates the rewarding effects of several drugs of abuse (Vlachou and Markou, 2010). Although there is clear role for GABAB receptor modulation of the hedonic effects of drugs of abuse, relatively little is known about GABAB receptor modulation of stress-induced anhedonia. Nevertheless, one study reported that reductions in sucrose preference induced by chronic mild stress in rats were prevented by chronic treatment with a GABAB receptor antagonist (Nowak et al., 2006), and we have shown that GABABð1aÞ-=- mice are more susceptible, whereas GABABð1bÞ-=- mice are more resilient to stress-induced anhedonia (O’Leary et al., 2014). Taken together, stress-induced differential neuronal activity patterns in the VTAnucleus accumbens reward system of the brain in GABABð1bÞ-=- and GABABð1aÞ-=- mice may at least partially contribute their differential susceptibility to stress-induced anhedonia although this has yet to be directly tested by inhibiting these isoforms specifically in the nucleus accumbens or VTA. One of the most robust genotype-dependent effects of acute stress on c-Fos expression was observed in the hippocampus (O’Leary et al., 2014), a key brain area involved in regulation of the stress response (Jacobson and Sapolsky, 1991; Brown et al., 1999) whereby the number of cFos-positive cells in response to acute stress was significantly increased in GABABð1bÞ-=- mice compared with wild-type and GABABð1aÞ-=- mice. This enhanced stress-induced c-Fos activation was most apparent in the dentate gyrus and ventral CA3 regions of the hippocampus and occurred to the same extent in both nonseparated and maternally separated GABABð1bÞ-=- mice. Interestingly, GABABð1aÞ-=- mice exhibited decreased stress-induced c-Fos in the ventral CA3, and this effect was not apparent when they had undergone prior maternal separation. Together, this suggests that GABAB receptors in the hippocampus might be important in the differential response to stress, and this observation is further supported by our findings (described in the next section) that maternal separation stress differentially affects adult hippocampal neurogenesis in GABABð1bÞ-=- versus GABABð1aÞ-=- mice. Finally, we also observed that GABABð1bÞ-=- mice exhibited enhanced stress-induced neural activation in the DRN irrespective of whether they had undergone prior maternal separation or not, but unlike the hippocampus, these increases were largely restricted to comparisons with GABABð1aÞ-=- and not wild-type mice (O’Leary et al., 2014). As described earlier in this chapter, there is accumulating evidence of a GABAB-serotonin interactions in the DRN (Cornelisse et al., 2007; Slattery et al., 2005; Takahashi et al., 2010), and the DRN plays a role in stress resilience (Challis et al., 2013). Taken together, this supports the hypothesis that GABAB receptors in the DRN may play a role in stress resilience. Within this context, however, it is noteworthy that it is the GABAB1a isoform rather than the GABAB1b isoform that is mainly expressed on serotonergic cells bodies DRN (Bischoff et al., 1999) and yet we did not observe any differences in stress-induced c-FOS expression in GABABð1aÞ-=- mice when compared with wild-type mice.
Adult hippocampal neurogenesis: a mechanism for resilience? Neurogenesis, the birth of new neurons, occurs in just a few areas of the adult brain including the dentate gyrus of the hippocampus, and several extrinsic factors can alter the
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proliferation and survival of these adult-born neurons including stress and chronic antidepressant treatments (Kempermann et al., 2015; Bergmann et al., 2015; Christian et al., 2014; Malberg et al., 2000; O’Leary et al., 2013). Moreover, there is emerging evidence that these adult-born hippocampal neurons may play a role in buffering the stress response as well as antidepressant regulation of the HPA axis (Levone et al., 2015; Snyder et al., 2011; Surget et al., 2011). Accumulating evidence suggests that the GABAB receptor also modulates adult hippocampal neurogenesis (Felice et al., 2012; O’Leary et al., 2014; Giachino et al., 2014). GABAB1-=- mice exhibit increased adult hippocampal progenitor cell proliferation as well as accelerated neuronal differentiation when compared with their wild-type counterparts (Giachino et al., 2014). In addition, we have shown that a GABAB receptor antagonist, CGP52432, which has antidepressant-like behavioral effects in the FST increased hippocampal cell proliferation in mice (Felice et al., 2012). Interestingly, we observed that the effect of CGP52432 on hippocampal cell proliferation occurred in the ventral rather than the dorsal hippocampus. This finding is intriguing in light of a growing body of evidence that suggests the hippocampus is functionally segregated along its longitudinal axis into dorsal and ventral regions, whereby the dorsal hippocampus (dHi) plays a predominant role in the spatial learning and memory, whereas the ventral hippocampus (vHi) plays a predominant role in the regulation of emotion-related processes (Bannerman et al., 2004; Fanselow and Dong, 2010). Moreover, there is emerging evidence that adult neurogenesis may also be differentially regulated along this axis with the effects of stress on neurogenesis occurring predominantly in the vHi (Tanti and Belzung, 2013; O’Leary and Cryan, 2014; O’Leary et al., 2012). Given the impact of stress and the GABAB receptor on adult hippocampal neurogenesis, and the identification of the hippocampus as a key brain area expressing altered neuronal responses to stress (as measured by c-Fos expression) in GABABð1bÞ-=- versus GABABð1aÞ-=mice, we examined whether increased adult hippocampal neurogenesis may contribute to the stress-resilient phenotype of the GABABð1bÞ-=- mice (O’Leary et al., 2014). We found that male GABABð1bÞ-=- mice exhibit increased proliferation of newly born cells in the vHi but not dHi. We also found that these stress-resilient GABABð1bÞ-=- mice exhibited increased survival of new adult-born cells in the hippocampus. Interestingly, we found that under baseline conditions, this increase in the survival of new adult-born cells occurred in the dHi but not the vHi, but in GABABð1bÞ-=- mice that had undergone early-life stress (maternal separation), this increased survival of new adult-born cells shifted from the dorsal to the ventral hippocampus. Thus, further supporting the emerging view that adult neurogenesis in the vHi rather than the dHi plays a predominant role in the response to stress. GABABð1bÞ-=- mice were also resistant to the early-life stress-induced decrease in the survival of adult-born cells in the vHi, thus suggesting a possible mechanism underlying their stress-resilient behavioral phenotype. Using female mice, we confirmed that increased adult hippocampal neurogenesis occurs in GABABð1bÞ-=- mice, whereas no differences were observed between GABABð1aÞ-=mice and wild-type mice. This finding also suggests that the increases in adult hippocampal neurogenesis observed in GABABð1bÞ-=- mice is not sex dependent and thus parallels the sex-independent stress-resilient behavioral phenotype observed in these mice (O’Leary et al., 2014).
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The mechanisms underlying GABAB receptor modulation of adult hippocampal neurogenesis are not yet known but may involve regulation of brain-derived neurotrophic factor (BDNF). BDNF is a neurotrophin involved in adult hippocampal neurogenesis. Moreover, it is required for antidepressant-induced increases in adult hippocampal neurogenesis and antidepressant-like behavior, and it also plays a role in stress resilience (O’Leary and Castren, 2010; Sairanen et al., 2005; Saarelainen et al., 2003; Berton et al., 2006; Krishnan et al., 2007; Bjorkholm and Monteggia, 2016). GABAB receptor antagonists have been shown to elevate BDNF protein and mRNA levels in various brain regions including the hippocampus (Heese et al., 2000; Enna et al., 2006). Thus, it will be of interest to determine whether the stress-resilient phenotypes of GABABð1bÞ-=- are due to enhanced BDNF signaling.
Conclusions In summary, GABAB1 receptor subunit isoforms differentially regulate stress resilience (Fig. 5.1). Reductions or deletions of GABAB1b are associated with an antidepressant-like behavioral phenotype and resilience to psychostress-induced anhedonia and psychosocial stress-induced social avoidance, whereas increased hippocampal GABAB1b expression in the hippocampus has been found in a genetic mouse model of depression. On the other hand, mice lacking the GABAB1a receptor subunit isoform are more susceptible to stressinduced anhedonia and social avoidance. Experiments using c-Fos immunohistochemistry to delineate the neural circuitry underlying the differential stress sensitivity of GABABð1bÞ-=and GABABð1aÞ-=- mice suggest that the VTA-nucleus accumbens reward pathway, the DRN, and the hippocampus are likely key brain areas involved in this neural circuitry. Moreover, adult hippocampal neurogenesis and the serotonin neurotransmitter system have been shown to be differentially affected in GABABð1aÞ-=- and GABABð1bÞ-=- mice. Taken together, the GABAB1a and GABAB1b subunit isoforms represent potential novel therapeutic targets for the treatment of stress-related psychiatric disorders.
Acknowledgements We thank Dr. Daniela Felice for assistance in creating Fig. 5.1.
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