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Chattopadhyay A, editor. Serotonin Receptors in Neurobiology. Boca Raton (FL): CRC Press/Taylor & Francis; 2007.

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Chapter 9Use of Mice with Targeted Genetic Inactivation in the Serotonergic System for the Study of Anxiety

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ROLE OF THE 5-HT SYSTEM IN MODULATING ANXIETY STATES

Anxiety is a normal reaction to threatening situations, and it represents a physiological protective function. Anxiety is often manifested as avoidance of threatening situations and is also characterized by overt sympathetic reactions. Pathological anxiety is a level of anxiety that is disproportionate to the threat and can be manifested even in the absence of threat. Individuals seem to have a consistent level of anxiety over their lifetime suggesting the importance of genetic factors. DSM-IV (American Psychiatric Association, 1994) and the International Classification of Diseases [ICD-10] (World Health Organization, 1992), two categorical systems, set the boundary at which a particular level of anxiety becomes an anxiety disorder. These boundaries are often based on the number and the duration of symptoms. DSM-IV provides diagnostic criteria for anxiety disorders, including panic disorder (PD), specific and social phobias, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and generalized anxiety disorder (GAD) (American Psychiatric Association, 1994; Noyes, 2004).

The 5-HT system has been implicated in the modulation of anxiety levels; some components of the 5-HT system promote anxiety whereas others reduce its symptoms. However, the 5-HT is only one of the many systems that have been implicated in anxiety disorders and GABA, norepinephrine, dopamine, and neuropeptides including corticotropin-releasing hormone, cholecystokinin, and neuropeptide Y have been shown to modulate anxiety.

The level of 5-HT is regulated by both the 5-HT transporter and the 5-HT1A autoreceptor (in the serotonergic raphe nuclei) (Blier et al., 1998; Inoue et al., 2004). Inhibiting the 5-HT transporter by selective serotonin reuptake inhibitors (SSRIs) is an effective treatment for certain anxiety disorders and depression (Blier et al., 1998; Inoue et al., 2004), whereas partial 5-HT1A receptor agonists such as buspirone have an anxiolytic effect (Goldberg et al., 1983). The 5-HT-mediated anxiolytic actions of these drugs do not in any way support the role of the 5-HT system in the pathogenesis of anxiety disorders. More compelling are the findings of recent genetic studies demonstrating a relatively small but significant increase in neuroticism in individuals who carry the s/s (short promoter repeat) alleles of the 5-HT transporter as compared to individuals with s/l (long) or l/l alleles (Lesch et al., 1996). Further studies and a recent meta-analysis of these studies found a moderate but significant association between the s allele and measures of anxiety (Sen et al., 2004; Munafo et al., 2004). A more robust effect of the s allele was seen in neuroimaging studies when amygdala activation was measured to fearful and angry human facial expressions (Hariri et al., 2002). These data are somewhat surprising because the s allele is associated with decreased transporter activity (and presumably more synaptic 5-HT), whereas pharmacological inhibition of the 5-HT transporter by SSRIs results in an anxiolytic effect. It has been hypothesized that a constitutive increase in 5-HT levels, specifically during development, leads to the increase in anxiety.

The involvement of the 5-HT system in the pathogenesis of anxiety disorders is also supported by the association between reduced 5-HT1A receptor levels in the anterior cingulate, posterior cingulate and raphe in PD and PTSD (Lesch et al., 1992; Lopez et al., 1998; Mann, 1999; Lemonde et al., 2003; Neumeister et al., 2004).

MICE WITH TARGETED GENETIC INACTIVATION IN THE SEROTONERGIC SYSTEM FOR THE STUDY OF ANXIETY

Although the association studies mentioned above have the potential of discovering disease-predisposing genes, the small contribution of individual genes and the variability of their effects make the discovery of these genes rare and difficult. In contrast, knockout technology allows the creation of genetic abnormalities in a large number of animals with the same genetic background (where variability in gene–gene interaction is not a factor). These animals can be tested for behavioral alterations under identical environmental conditions that is also important in finding small effects. A further advantage is that mouse knockout models are amenable for mechanistic studies to reveal the molecular and cellular pathways underlying a specific behavior.

BEHAVIORAL TESTS FOR ANXIETY

Anxiety cannot be easily reproduced in animals, but it is possible to create conditions resembling anxiety disorders, especially with genetically modified mice. Fearful situations in animals elicit avoidance and the unwillingness to be exposed to novel situations are also common symptoms of anxiety disorders including GAD, PD, phobias, and PTSD. Therefore, fear reaction can conceptually be interpreted as anxiety-like behavior (Rodgers, 1997; Crawley, 1999; Weiss et al., 2000). As in humans, fear/anxiety in mice can be viewed as a behavior serving a protective function and an increase in the normal level of fear reaction as a result of a genetic manipulation may be interpreted as conditions similar to anxiety disorders.

Fear and anxiety-like behavior can be unconditioned or conditioned. Unconditioned tests often measure the natural conflict experienced by animals as they avoid or explore a novel, potentially dangerous environment for food, water, or social reward. Measurements of avoidant behaviors, such as decreased activity in a particular region of the testing apparatus, compared to overall activity, provide a quantifiable measure to assess the level of anxiety. Novel stressful situations include high platforms (elevated plus maze) (Lister, 1987) and a brightly lit area (open field, light–dark box) (Crawley, 1981; Treit and Fundytus, 1988). Animal models of conditioned fear on the other hand measure anxiety in environments associated with prior or present stress (Davis, 1990; Geller et al., 1962; Vogel et al., 1971). Similar to avoidance of unconditioned situations, avoidance of conditioned situations is also a characteristic symptom of PD, PTSD, and in some degree of all anxiety disorders. As unconditioned and conditioned anxiety tests are straightforward and relatively simple to conduct and interpret, they are frequently used in behavioral studies. More complex methods are also available, including social interaction tests that measure a different aspect of avoidant behavior that is highly relevant to some anxiety disorders (for example social phobias) (File, 1985). Additional information on anxiety-related tests can be found in several excellent reviews (Griebel, 1995; Rodgers, 1997; Rodgers et al., 1997; Weiss et al., 2000; Uys et al., 2003).

MICE WITH GENETIC INACTIVATION OF 5-HT RECEPTORS AND THE 5-HT TRANSPORTER

5-HT receptors mediate the pre- and postsynaptic actions of 5-HT and are classified into seven groups (5-HT1–7), comprising a total of at least 14 structurally and pharmacologically distinct mammalian receptor subtypes (Hoyer et al., 1994). At the molecular level, most 5-HT receptors are seven transmembrane-spanning, G-protein-coupled metabotropic receptors (Barnes and Sharp, 1999). The 5-HT3 receptor is the only member of the 5-HT receptor family that is a ligand-gated ion channel (Derkach et al., 1989).

The 5-HT transporter is central in the regulation of 5-HT activity in the brain. Following its release, 5-HT is taken up by presynaptically located 5-HT transporters for recycling or metabolic degradation. Under normal conditions, 5-HT transporter activity is the principal mechanism for clearing 5-HT from the synapse and extracellular space that consequently determines the duration and intensity of the 5-HT signal.

5-HT1A Receptor Knockout Mice

5-HT1A receptor knockout mice were generated on Swiss-Webster (SW), C57Bl6, and 129sv genetic backgrounds (Heisler et al., 1998; Parks et al., 1998; Ramboz et al., 1998). Independently of the genetic background, mutant mice exhibited anxiety-like behaviors (in open field, elevated plus, and zero maze) and reduced immobility in the forced swim test (Parks et al., 1998) or tail suspension test (Heisler et al., 1998; Ramboz et al., 1998). Later studies with 5-HT1A receptor knockout mice on the 129sv background also showed anxiety-like behavior in the novelty-induced suppression of feeding test and in fear conditioning (Gross et al., 2000; Klemenhagen et al., 2006). It was also shown that 5-HT1A receptor knockout mice have reduced locomotor activity, another sign of increased anxiety-like behavior (Gross et al., 2002). Increased autonomic arousal, a typical symptom of anxiety disorders, was also observed in these mice. For example, heart rate and body temperature was increased following footshock and saline injection in 5-HT1A receptor knockout mice (Gross et al., 2000; Pattij et al., 2002). These data demonstrate that 5-HT1A receptor knockout mice have abnormalities in three important measures of anxiety: increased avoidance, decreased locomotor activity, and increased autonomic arousal. Consequently, these studies firmly established the 5-HT1A receptor as a modulator of anxiety, at least in mice.

Altered sleep pattern is also a characteristic abnormality in anxiodepressive diseases, and 5-HT1A receptor knockout mice have been shown to have altered sleep–wake regulation. Specifically, rapid eye movement (REM) sleep was enhanced in 5-HT1A receptor knockout mice during both the light and the dark phases, whereas slow wave sleep was unaltered (Boutrel et al., 2002).

In addition to anxiety-related phenotypes, data indicate a hippocampal-dependent learning and memory deficit in 5-HT1A receptor knockout mice. Behavior of mutant mice on the SW background is impaired in the hidden platform (spatial) version of the Morris water maze and the delayed version of the Y maze (Sarnyai et al., 2000). In contrast, nonhippocampal memory tasks such as the visible platform (nonspatial) version of the Morris water maze, the immediate version of the Y maze, and the spontaneous-alternation test of working memory were normal in 5-HT1A receptor knockout mice. 5-HT1A receptor knockout mice on the 129sv genetic background showed a similar phenotype but the abnormality was apparent in older (22-month-old) but not in young (3-month-old) mice (Wolff et al., 2004). As the mice in the Sarnyai et al. study (Sarnyai et al., 2000) were 4–6 months old, it may take a certain degree of aging when the learning and memory defect becomes apparent in 5-HT1A receptor knockout mice. Alternatively, there are baseline differences among mouse strains in Morris water maze performance (Clapcote and Roder, 2004) that could influence the onset of the learning and memory deficit in 5-HT1A receptor knockout mice.

It is important to note that acute pharmacological inhibition of the 5-HT1A receptor does not result in an anxiety-like phenotype (Millan, 2003). Consistent with this, knockout mice with an adult-specific receptor loss showed no anxiety-like phenotype. Only when receptor expression was inactivated during early postnatal life mice developed anxiety that persisted through life (Gross et al., 2002). The development-specific effects of receptor inactivation, however, does not apply to the 5-HT1A receptor mediated regulation of REM sleep because pharmacological blockade of the receptor by the selective antagonist WAY 100635 promoted REM sleep similar to the effect of the genetic inactivation (Boutrel et al., 2002). This indicates a direct role of the 5-HT1A receptor in the regulation of REM sleep.

The brain regions associated with the development of the anxiety-like phenotype in 5-HT1A receptor knockout mice are important to determine if we want to understand the neuronal circuitries underlying this phenotype. Although hippocampal (in particular dorsal hippocampal) dysfunction has traditionally been associated with spatial cognitive tasks, data also indicate a ventral hippocampal involvement in anxiety-like behavior (Moser and Moser, 1998; Kjelstrup et al., 2002). Consistent with the behavioral abnormalities that can be linked to the hippocampus, 5-HT1A receptor knockout mice show electrophysiological alterations in the hippocampus. Paired-pulse facilitation and paired pulse inhibition were impaired in the dentate gyrus and CA1 region of the hippocampus of SW 5-HT1A receptor knockout mice, respectively (Sarnyai et al., 2000; Sibille et al., 2000). Another study demonstrated an increase in theta oscillations in 5-HT1A receptor knockout mice on the 129sv genetic background during the exploration of the open arm of the elevated plus maze (Gordon et al., 2005). Theta oscillations are 4–12 Hz waves present in local field potentials recorded throughout the hippocampus during navigation (Buzsaki, 2002). Also, 5-HT1A receptor knockout mice displayed higher limbic excitability manifested as lower seizure threshold and higher lethality in response to kainic acid administration (Sibille et al., 2000). Another brain region that may be involved in the anxiety-like phenotype of 5-HT1A receptor knockout mice is the prefrontal cortex (PFC). PFC malfunction was detected in anxiety disorders (Malizia et al., 1998; Bremner et al., 2000; Bystritsky et al., 2001; Dilger et al., 2003) and increased neuronal activity was associated with anxiety in animals (Shah and Treit, 2003; Singewald et al., 2003; Shah and Treit, 2004). Reductions in GABAA receptor expression were reported in 5-HT1A receptor knockout mice on the SW background (Bailey and Toth, 2004) while changes in glutamate and GABA uptake were found in knockout mice on the C57Bl6 background (Bruening et al., 2006). This demonstrates that the inactivation of the 5-HT1A receptor elicits different and genetic-background-dependent perturbations in the prefrontal cortex GABA/glutamate system. These perturbations can result in a change in the balance between excitation and inhibition on both genetic backgrounds and may contribute to the anxiety phenotype of 5-HT1A receptor knockout mice.

The electrophysiological and biochemical studies summarized above are consistent with a role for 5-HT1A receptors at the postsynaptic sites in anxiety-related behaviors. 5-HT1A receptors are expressed both presynaptically on 5-HT neurons in the raphe nuclei as somatodendritic autoreceptors and postsynaptically in 5-HT target areas (such as hippocampus and cortex). Although it seems plausible that lack of the presynaptic receptors results in an increase in 5-HT leading to the anxiety phenotype, several lines of evidence suggest that it is rather the absence of postsynaptic 5-HT1A receptors that can be linked to the anxiety phenotype. First, basal 5-HT levels are not altered, as measured by in vivo microdialysis, in 5-HT1A receptor knockout mice (He et al., 2001; Bortolozzi et al., 2004). Second, expression of 5-HT1A receptors in forebrain regions (at the postsynaptic sites) rescued the anxiety phenotype of 5-HT1A receptor knockout mice (Gross et al., 2002).

In summary, experiments with 5-HT1A receptor knockout mice clearly demonstrate that the expression of the receptor is essential for the establishment and/or maintenance of a normal level of anxiety. Data indicate the involvement of a 5-HT1A receptor-dependent early postnatal developmental process in the anxiety-like phenotype of 5-HT1A receptor knockout mice, but the actual neurobiological process is still unknown.

5-HT1B Receptor Knockout Mice

In contrast to the genetic inactivation of the 5-HT1A receptor, knockout of the 5-HT1B receptor resulted in a reduced anxiety level in an open field test and in the novelty-induced suppression of feeding test (Zhuang et al., 1999). However, the light–dark box and elevated plus maze tests showed no significant change in anxiety-like behavior in the 5-HT1B receptor knockout mice (Malleret et al., 1999; Phillips et al., 1999). Moreover, the reduced anxiety phenotype of 5-HT1B receptor knockout mice could not be reproduced in various laboratories, even using the same supply of mice (Phillips et al., 1999) indicating that the phenotype is not robust and/or there are confounding, such as environmental, factors that may strongly influence the phenotype. The 5-HT1B receptor may also be involved in regulating sleep because its inactivation increased REM sleep (Boutrel et al., 1999). The rather limited anxiety-related phenotype of 5-HT1B receptor knockout mice is surprising because the receptor is widely expressed in both presynaptic and postsynaptic locations (Gothert, 1990; Boschert et al., 1994). It has been proposed that the lack of a robust anxiety-related phenotype in 5-HT1B receptor knockout mice is the result of adaptive changes in the coupling of 5-HT1A and 5-HT2C receptors (Knobelman et al., 2001; Ase et al., 2002; Clifton et al., 2003).

5-HT2 Receptor Knockout Mice

Similarly to 5-HT1A receptor specific drugs, compounds that target the 5-HT2A receptors are widely used in the treatment of depression and schizophrenia. Also, 5-HT2A receptor antagonists have an anxiolytic profile in a number of behavioral paradigms (Stutzmann et al., 1991; Motta et al., 1992; Costall and Naylor, 1995). Consistent with the pharmacological data, global disruption of 5-HT2A receptors in mice resulted in a reduced level of anxiety in various conflict-based tests, including the elevated plus maze, open field and the light–dark shuttle test (Weisstaub et al., 2006). These data indicate that it is the direct effect of the receptor loss rather than the absence of the receptor during developmental that leads to the knockout phenotype. The genetic inactivation of the receptor did not alter fear-conditioning and depression-related (forced swim and tail suspension) behaviors. This finding is surprising because antisense-mediated downregulation of the 5-HT2A receptor decreased immobility in the forced swim test (Sibille et al., 1997). Similarly, pharmacological blockade of the receptor decreases immobility (Patel et al., 2004), and treatment with antidepressants downregulates the 5-HT2A receptor and results in less immobility. The different behavioral outcomes of the genetic inactivation and the antisense knockdown/pharmacological blockade of the receptor suggest that developmental changes in knockout mice blunt the effect of the receptor deficit on depression-related behavior.

Selective cortical re-expression of the 5-HT2A receptor rescued the reduced anxiety-like behavior of 5-HT2A receptor knockout mice, indicating a role for cortical 5-HT2A receptors in the modulation of conflict based anxiety-related behavior (Weisstaub et al., 2006).

Genetic inactivation of another member of the 5-HT2 receptor family, the 5-HT2B receptor, results in embryonic and neonatal death caused by heart defects (Nebigil et al., 2000), and therefore a possible role for the receptor in anxiety is impossible to study by conventional knockout. Genetic inactivation of still another member of the family, the 5-HT2C receptor, indicated the involvement of the receptor in food intake (Chou-Green et al., 2003b, a; Tecott and Abdallah, 2003). It was proposed that these mice may model weight gain seen in depression and compulsive disorders.

5-HT3 Receptor Knockout Mice

The only ionotropic 5-HT receptor, the 5-HT3 receptor, has also been linked to anxiety-like behavior by using targeted mutagenesis. 5-HT3 receptor deficient mice exhibit reduced anxiety-like behavior in the elevated plus maze and light dark shuttle box (Kelley et al., 2003). As pharmacological blockade of the receptor results in an anxiolytic profile in behavioral tests (Costall and Naylor, 1992), the receptor seems to directly regulate anxiety levels in mice. The reduced anxiety-like phenotype of 5-HT3 receptor knockout mice is similar to that of the 5-HT2A receptor knockout mice and opposite to that of the 5-HT1A receptor-deficient mice, indicating that some 5-HT receptors increase while others reduce anxiety levels.

5-HT4–7 Receptor Knockout Mice

Genetic inactivation of the 5-HT4 receptor resulted in reduced locomotor activity in novel environment but increased feeding following stress (Compan et al., 2004). It was concluded that 5-HT4 receptors modulate feeding and activity in stressful situations and are perhaps involved in eating disorders.

Of the two subtypes of 5-HT5 receptor, 5-HT5A and 5-HT5B, only the former is present in human CNS (Grailhe et al., 1999; Grailhe et al., 2001). 5-HT5A knockout mice exhibit increased exploratory activity when exposed to novel environment but show no change in anxiety-related behaviors in several behavioral paradigms (Grailhe et al., 1999; Grailhe et al., 2001).

Deletion of the 5-HT6 receptor resulted in no abnormal behavioral phenotype tested in numerous behavioral assays including models of anxiety (Bonasera et al., 2006). The only demonstrated abnormality of 5-HT6 receptor knockout mice is a reduced sensitivity to ethanol (Bonasera et al., 2006).

Pharmacological studies showed no clear evidence for the involvement of the 5-HT7 receptor in anxiety-related behavior but suggested a role for the receptor in sleep. Consistent with these pharmacological data, 5-HT7 receptor knockout mice spent less time in, and had less frequent episodes of, REM sleep, behaviors opposite to that observed in depression (Hedlund et al., 2005). 5-HT7 receptor knockout mice have less immobility in the forced swim and tail suspension tests that also indicate that the receptor modulates behavior related to depressive states. This behavior could also be reproduced by the selective pharmacological blockade of the receptor. This indicates that both the regulation of sleep pattern and depression-related behaviors may be directly linked to the activation of the 5-HT7 receptor.

5-HT Transporter Knockout Mice

Although individuals with the s/s 5–HT transporter alleles seems to have an increased susceptibility to neuroticism and anxiety (see Introduction), initial studies with 5-HT transporter knockout mice indicated no anxiety-like phenotype (Bengel et al., 1998). A later study showed anxiety, at least in females, in 5-HT transporter knockout mice (Murphy et al., 2001). A more recent analysis of these mice demonstrated anxiety in some (latency to feed in novel environment) but not other behavioral paradigms (the open field and elevated plus maze tests) (Lira et al., 2003). Another study however reported increased anxiety-like behavior of the 5-HT transporter knockout mice in the elevated plus maze and light–dark transition test (Holmes et al., 2003). Although the difference in the genetic background may have accounted for this discrepancy, these studies nevertheless indicate that the 5-HT transporter null phenotype is relatively weak. This is not entirely surprising considering the small contribution of the s allele in neuroticism and anxiety in humans (Lesch et al., 1996).

Mice null for the 5-HT transporter have secondary adaptive alterations in the 5-HT system. Specifically, the density and expression, but not G-protein coupling, of 5-HT1A receptor were reduced in 5-HT transporter knockout mice (Li et al., 2000). This finding is consistent with the reduced 5-HT1A receptor binding in individuals with the s allele of the 5-HT transporter (David et al., 2005). The reduced 5-HT1A receptor level in 5-HT transporter knockout mice may actually contribute to the anxiety-like phenotype as inactivation of this receptor results in a robust, anxiety-like phenotype (see above). Indeed, it has been shown that expression of 5-HT1A receptors by adenovirus-mediated gene transfer in the medial hypothalamus rescues the increased stress response (measured as exaggerated adrenocorticotropin responses) and reduced locomotor activity of 5-HT transporter knockout mice (Li et al., 2004). It is not known if limbic (for example, amygdalar and hippocampal) expression of the receptor would rescue the anxiety-like phenotype of 5-HT transporter knockout mice.

The anxiety-like phenotype of 5-HT transporter knockout mice was more robust when BDNF was also genetically inactivated (Ren-Patterson et al., 2005). In addition to a higher level of anxiety-like behavior, double knockout mice, as compared to 5-HT transporter knockout, BDNF heterozygote knockout and wild-type mice, displayed significantly reduced levels of 5-HT and 5-hydroxyindole acetic acid in the hippocampus and hypothalamus, and greater increases in plasma ACTH after a stressful stimulus. These data are consistent with the notion that anxiety disorders are polygenic characterized by individually small contributions from several genes.

As pharmacological blockade of the 5-HT transporter has an anxiolytic profile, the increased anxiety-like behavior of 5-HT transporter knockout mice was presumed to be related to the absence of 5-HT transporter during development. This notion received support recently because the pharmacological blockade of 5-HT transporter during early postnatal life also elicited anxiety-like behavior in adults (Ansorge et al., 2004). This scenario is similar to that observed with the 5-HT1A receptor because receptor loss resulted in an anxiety-like phenotype only if absent during early postnatal life.

SUMMARY

The first knockout of a 5-HT receptor was published more than 10 years ago and since then most of the 5-HT receptors have been genetically inactivated in mice. Reviewing the anxiety-related behavior of individual receptor knockout lines, it is apparent that genetic inactivation of some receptors, including the 5-HT2A and 5-HT3 receptors, reproduced the phenotype elicited by the acute pharmacological blockade of the receptor. This indicates that signaling through some 5-HT receptors is directly involved in the regulation of anxiety states. In other cases, however, the genetic inactivation and pharmacological blockade of the receptor resulted in different and sometimes opposing behaviors. For example, the genetic inactivation of the 5-HT transporter results in increased anxiety whereas chronic pharmacological blockade of the 5-HT transporter by SSRIs leads to reduced anxiety. Mice null for the 5-HT1A receptor show increased anxiety, while selective pharmacological inhibitors of the receptor do not have a measurable effect on anxiety in adult mice. These are interesting findings because the genetic inactivation of the receptor could be similar to inherited conditions characterized by a loss of function mutation of the receptor/transporter. Indeed, 5-HT transporter knockout in mice may reproduce the s polymorphism in humans. Also, certain individuals have a reduced expression of the 5-HT1A receptor that, if present from early life, is similar to the null mutation of the receptor in mice. Therefore, the 5-HT1A receptor and 5-HT transporter knock-out mouse strains may represent disease models that can be used to understand how a receptor or transporter deficiency leads to an anxiety-like phenotype.

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