Modeling Tourette Syndrome In Rodents

Because the genetic and pathophysiological etiologies of TS are unknown, no animal models of the disorder exist that have true construct validity (McKinney, 1998). However, investigators have a variety of methods that can induce abnormal repetitive movements in rodents that mimic elements of tic behavior. Stereotypies are simple or complex movement sequences that are repeated excessively, invari-antly, and purposelessly (Ridley, 1994; Mason, 1991). These behaviors are species specific and emerge when an animal is subjected to stress or confinement in a low stimulus environment such as a zoo or laboratory animal colony (Ridley, 1994; Mason, 1991). For example, laboratory mice housed in propylene bins frequently engage in "cage stereotypies" such as mouthing the bars of the wire cage top (Wurbel, 2001; Garner and Mason, 2002). It is generally accepted that stereotypies develop from functional, motivated behaviors such as foraging or defense that are normally terminated when the goals (food, escape) are achieved (Dantzer, 1991; Wurbel, 2001). In captive situations, these goals are repeatedly frustrated, and sensory feedback from the motor behaviors serves to trigger further execution of the behaviors in the absence of motivation or environmental stimulus (Dantzer, 1991).

Garner and Mason (2002) provided compelling evidence that stereotypical behaviors reflect disorders of basal ganglia dysfunction. These investigators hypothesized that if stereotypies emerge as a result of disinhibition of behavioral selection, other behaviors mediated by the basal ganglia should also show evidence of disinhibition. Garner and Mason (2002) reported that caged voles expressing stereotypies also had enhanced rates of behavioral initiation, increased impulsivity, impaired extinction learning, and increased "knowledge-action" dissociation—the inability to suppress a previous incorrect response despite knowledge of the correct response. These results are consistent with behavioral findings of impulsivity and inattention in individuals with TS (Leckman, 2002).

A. Measuring Stereotypies in Rodents

Stereotypic behavior in rodents can be elicited by a variety of methods, including isolation rearing, lesioning of specific brain structures, administration of drugs that affect CSTC neurotransmission, and, more recently, genetic manipulations (Ridley, 1994; Campbell et al., 1999). Despite the diversity of induction procedures, methods used to evaluate stereotypical behaviors are essentially similar. Observers who are blind to the experimental conditions test the animal either in its home cage or in a special test chamber. Behavior ratings can be categorical, recording the presence or absence of a specific behavior, or quantitative, measuring the frequency and duration of each behavior. Most behavior rating scales are based on the Creese-Iverson stereotypy scale (Creese and Iverson, 1973). This scale consists of six categories of behavior: 0) asleep or motionless; 1) active, moving about the cage; 2) predominantly active with bursts of stereotyped activity; 3) stereotyped activity occurring along a fixed path; 4) stereotyped behaviors occurring in one location of the cage with sniffing or rearing in one location; 5) stereotyped behavior in one location, with bursts of gnawing or licking; and 6) continual gnawing or licking of the cage. This scale was developed from behavioral observations of rats exposed to increasing doses of amphetamine, and behaviors such as sniffing, licking, and gnawing are species specific and selectively promoted by amphetamine. Substitution of other repetitive behaviors is necessary in evaluating other species.

Behavioral scoring is often done in real time, using at least two observers blind to treatment conditions. However, because some orofacial movements may be subtle and easily missed, videotaping the observation sessions is preferred. The most common method of scoring uses time sampling procedures, in which investigators record behavior over a specified time at predetermined intervals in the testing session. For example, in our laboratory, we record animal behaviors over a one-minute period, at five-minute intervals in a thirty-minute test session.

In addition to the traditional observation methods described here, automated methods of stereotypy detection and analysis are now available that appear to offer greater sensitivity and ease of use (Campbell et al., 1998; Fowler, 2001).

B. Psychostimulant Model

The "dopamine hypothesis" of TS holds that excessive dopaminergic transmission in corticostriatothalamic (CSTC) circuits is responsible for the pathophysiology of TS. This hypothesis developed largely from clinical observations that drugs that block dopamine D2 receptors relieve tic symptoms in the majority of TS patients (Challas, 1967; Shapiro and Shapiro, 1988; Shapiro et al., 1989). Drugs that block dopamine synthesis or vesicular uptake were also reported to be helpful (Sweet et al., 1974; Jankovic et al., 1984), while drugs that increased synaptic dopamine concentrations often worsened tic symptoms (Erenberg et al., 1985). However, aside from these pharmacologic studies, little evidence supports the presence of dopaminergic abnormalities in TS patients. Early reports of decreased concentrations of homovanillic acid (HVA), the major dopamine metabolite in the cerebrospinal fluid of TS patients (Butler et al., 1979; Cohen et al., 1978; Singer et al., 1982) have been contradicted by more recent findings in a comprehensive study of TS, OCD, and control populations (Leckman et al., 1995). Postmortem examinations of brain dopamine and HVA concentrations, as well as tyrosine hydroxylase activity, have also failed to identify differences between TS and control populations (Anderson et al., 1992a,b). However, recent PET and SPECT imaging studies examining dopamine release have provided intriguing but inconclusive evidence of changes in dopamine receptor densities and phasic dopamine release in TS patients (reviewed in Singer and Wendlandt, 2001).

1. Description of the Model

Since the first report that amphetamine induces oral stereotypies in rodents, investigators have intensively studied psychostimulant effects on behavior and neuro-chemistry (Randrup et al., 1963). The ability of these drugs to reliably induce a set of characteristic behaviors in rodents provides an opportunity to examine the neural circuits and molecular mechanisms underlying behavioral disinhibition. The indirect dopamine receptor agonist amphetamine has been particularly well studied in this regard. Amphetamine increases synaptic dopamine concentrations through multiple mechanisms, including reversal of the synaptic and vesicular monamine transporters and inhibition of mono-amine oxidase (Florin et al., 1994).

The behavioral profiles elicited by acute systemic amphetamine administration have been well described (for reviews see Randrup and Munkvad, 1974; Robinson and Becker, 1986; and Florin et al. 1994). In low doses (0.3-1.5 mg/kg), amphetamine stimulates increased locomotor behavior, primarily vertical- (rearing) and forward-directed movements. At intermediate doses (1.5-2.5 mg/kg) these movements increase in frequency, but are interrupted by brief periods of decreased locomotion accompanied by repetitive head and limb movements and sniffing. Amphetamine doses greater than 2.5 mg/kg induce a behavior pattern characterized by an early and late phase of increased locomotor behavior separated by a prolonged period of stereotypy. During the stereotypy phase, the animal remains in a particular area of the cage and engages in repeated movements of the head and fore-limbs, and may continuously sniff, lick, or bite the cage or bedding. Repeated daily injections of amphetamine increase in the magnitude and duration of the locomotor and stereo-typy responses. In addition, at high doses, the interval to onset of the stereotypy phase is decreased.

2. Relevance to Tourette Syndrome

Although the psychostimulant model is not unique to TS, it has provided a wealth of information about the role of the basal ganglia in the release of normal and repetitive behaviors that has advanced understanding of this disorder. Thus this model continues to have considerable heuristic value in TS research. One significant recent finding is the discovery of a potential role for striosomes in the activation of stereo-typic behavior.

The relationship between stereotypies and striosomal activation may be the single most important recent discovery relevant to TS (Canales and Graybiel, 2000). Expression of immediate early genes such as fos and jun is a marker of neuronal activation in the striatum (Graybiel, 2000). Graybiel and colleagues had previously discovered that repeated administration of the psychostimulants amphetamine and cocaine increased the number of neurons expressing these markers (Graybiel et al., 1990). In an elegant series of studies, Graybiel and colleagues compared the amount of striatal immediate early gene expression with the intensity of stereotypy expression induced by repeated administration of amphetamine and cocaine (Canales and Graybiel, 2000). Results of this study showed that the ratio of striosomal to matrix activation was tightly correlated with the intensity of stereotypy expression (Canales and Graybiel, 2000). These findings suggested that in addition to the indirect-direct pathways regulating movement inhibition and release, another pathway exists that regulates movement frequency and selection (Canales and Graybiel, 2000). Striosomes receive cortical input from the limbic orbitofrontal and anterior cingulate cortex and project to the substantia nigra, thus regulating the availability of dopamine to the striatum

(Graybiel, 2000). Enhanced activation of striosomal neurons may promote stereotypy expression by altering normal patterns of reward and saliency signaling by corticostriatal and nigrostriatal pathways, decreasing the range of behaviors selected and increasing the repetition of those behaviors (Canales and Graybiel, 2000).

C. The Transgenic Model

While Graybiel's findings clearly established a role for the basal ganglia in the expression of stereotypies, they also emphasized the need to investigate cortical contributions to this behavior. Hyperactivation of glutamatergic cortical projection neurons has been proposed as a causative mechanism in TS and several lines of evidence support this hypothesis (Weeks, 1996). Seizures of the cingulate cortex, a secondary motor area associated with integration of motor and affective information give rise to involuntary vocalizations and orofacial movements (Levin and Duchowny, 1991; Mazars, 1970). PET scans show decreased perfusion in this area in TS patients, and fMRI showed increased signal intensity in this region during tic suppression. (Chase et al., 1986). The ability of most TS patients to voluntarily suppress their tics suggests involvement of the medial pre-frontal cortex, and imaging studies have shown an increase in basal glucose metabolism in the medial prefrontal and orbitofrontal cortices (Chase et al., 1986; Cunningham and Jones, 1993). Two studies using transcranial magnetic stimulation (TMS) have found evidence of abnormalities in the primary motor cortex of TS patients (Zieman et al., 1997; Greenberg et al., 2000).

1. Description of the Model

The D1CT-7 transgenic mouse is currently the best animal model for investigating the effects of cortical hyper-activity on stereotypy expression. This animal line, developed by Dr. Frank Burton at the University of Minnesota, expresses a transgene made by fusing the promoter region for the human D1 receptor with the enzymatic portion of cholera toxin subunit alpha 1 (A1) gene (Burton et al., 1991; Campbell et al., 1999). The A1 subunit catalyzes the transfer of an ADP-ribose moiety from NADH to the alpha subunit of activated heterotrimeric Gs proteins (Burton et al., 1991). Because ribosylation of Gs inhibits its intrinsic GTPase ability, the molecule remains in an irreversibly active state. The net cellular effect is hyperresponsiveness to all afferent stimuli and enhanced neurotransmitter release due to chronic activation of adenylate cyclase with elevation of cAMP levels and its associated downstream targets (Campbell, 1999).

Interestingly, despite the fact that D1 expression is highest in the basal ganglia, expression of the D1CT transgene is restricted to the piriform cortex layer II, and somatosensory cortex layers II-III, and the amygdalar intercalated nucleus (ICN) (Campbell, 1999). Neurons in these layers of the somatosensory and piriform cortex project laterally and also to deeper layer output neurons that innervate the dorsal and ventral striatum, respectively (Campbell, 1999). The ICN regulates excitatory output from the baso-lateral and central amygdaloid nuclei, which project to the prefrontal cortex and ventral striatum (Campbell, 1999).

The behaviors of D1CT-7 mice are consistent with heightened activity of the anatomical regions expressing the transgene. The mice are generally hyperactive and exhibit perseveration in all behaviors; however, in contrast to psy-chostimulant-induced stereotypies, D1CT-7 mice can be easily distracted during these behaviors (Campbell, 1999). Initial studies indicated that these mice exhibited behaviors that appeared to be primarily compulsive. For example, D1CT-7 mice of both sexes were observed to engage in persistent biting of themselves and their cage mates. However, "resident-intruder" behavioral assays revealed that D1CT-7 mice are actually less aggressive than control littermates; moreover, the biting behavior emerged prepubertally, and occurred during social grooming but not fighting (Campbell, 1999). Taken together, these findings indicated that biting behavior was likely to be analogous to trichotillomania, a hair-pulling compulsion related to TS and obsessive compulsive disorder (Van Ameringen et al., 1999; Campbell, 1999).

Recent behavioral studies indicate that in addition to compulsive behaviors, D1CT-7 mice exhibit repetitive jerking movements, or "twitches," of the head, trunk, and limbs that have several characteristics of tics (Nordstrom and Burton, 2002; McGrath et al., 2000). The twitches are simple or complex combinations ofjerking movements, and occurred in flurries (defined as twitches that occurred at intervals of five seconds or less). Interestingly, males exhibited more "tic flurries" than females. Like TS, the onset of twitching occurred developmentally, appearing as early as postnatal day 16 (Nordstrum and Burton, 2002). Finally, administration of clonidine, an alpha2 adrenergic agonist used for tic suppression in TS, significantly reduced the number of twitches in D1CT-7 mice (Nordstrum and Burton, 2002).

2. Relevance to Tourette Syndrome

Based on the above information, D1CT-7 mice appear to have the greatest behavioral homology to TS of any animal model reported so far. Further studies examining the neural substrates of the compulsive and tic-like behaviors of these mice may provide valuable insights into normal and abnormal mechanisms by corticostriatal loops that regulate behavioral selection and release. Moreover, the similarity of the D1CT-7 behaviors to tic behaviors suggests that this model may have good predictive validity in developing therapeutic drugs for the treatment of tics.

D. The Autoimmune Model

The hypothesis that infections may trigger tic disorders is not new. In 1929, Selling proposed that the majority of tics arise from ". . . toxic encephalitis due to absorption from an extracerebral focus" and presciently suggested treatment directed toward "early recognition and proper handling of infection" (Selling, 1929). However, research into the relationship between infections and tic disorders really began in the last decade, spurred in large part by a renewed interest in Sydenham chorea (SC) as a neuropsychiatric manifestation of poststreptococcal rheumatic fever.

SC is the most common acquired choreiform movement disorder of childhood, affecting females more often than males. Characteristic symptoms include rapid, involuntary contractions of facial, trunk, and limb muscles, but children with SC often display tics, emotional lability, and symptoms of obsessive compulsive and attention deficit disorders (Swedo, 1994; Mercadante, 2000). A finding key to understanding how streptococcal infection could produce motor and psychiatric symptoms was the discovery of antibodies in the serum of SC patients that reacted with basal ganglia nuclei and streptococcal antigens (Husby, 1976). Kiessling and colleagues (1993) hypothesized that a similar "molecular mimicry" could be the pathogenic mechanism in some cases of TS and OCD. Antineuronal antibodies were present in the sera from a cohort of children with recent onset of tics following streptococcal infections. In 1998, National Institute of Mental Health (NIMH) defined a new diagnostic subgroup of individuals with childhood onset tics and OCD: pediatric autoimmune neuropsychiatry disorders associated with streptococcal infection (PANDAS) (Swedo et al., 1998). Criteria for diagnosis included the presence of tics or OCD symptoms with a prepubertal onset, evidence of streptococcal infection, episodic symptom severity, and neurological abnormalities (Swedo et al., 1998).

Molecular mimicry, or binding of streptococcal antibodies to human basal ganglia epitopes, remains the proposed mechanism for post streptococcal tic expression in PANDAS patients. One hypothesis suggests that children expressing high levels of the B-cell surface receptor D8/17 are more vulnerable to developing rheumatic fever and neuropsychiatric disorders following Group A beta-hemo-lytic streptococci (GABHS) infection (Bessen, 2001).

1. Description of the Model

To establish a causal role for autoantibodies in the pathogenesis of TS, it was necessary to demonstrate that passive transfer of serum from TS patients would induce ticlike behaviors in animal models (Archelos, 2000). Hallett and colleagues (2000) were the first to report the induction of stereotypy expression following infusion of sera into the striatum of adult male rats. In this procedure, cannulae were stereotaxically implanted into the striatum of anesthetized rats. After a one-week recovery period to allow reestablishment of the blood brain barrier, the animal was again anesthetized and the cannulae were connected to polyethylene tubing filled with serum from TS patients or normal controls. The serum was driven through the cannulae by an osmotic pump implanted subcutaneously in the animal's back. Behavior was scored every day for the three days of serum infusion, and for three days after the infusion was stopped. Results of behavior scoring showed that during the period of infusion, animals that received TS sera exhibited significant increases in licking and ultrasonic vocalizations as compared to controls (Hallett et al., 2000). During the post infusion period, licking and head shaking were significantly increased in this group as compared to controls (Hallett et al., 2000).

A subsequent study by Taylor and colleagues (2002) compared induction of oral stereotypies in rats infused with TS sera containing high levels of autoantibodies, TS sera with low levels of autoantibodies, and sera from normal controls. In this study, the cannulae were implanted in the ven-trolateral striatum, a region associated with the expression of oral behaviors (Kelley et al., 1988). Results of this study also showed significant increases in oral stereotypy expression in rats receiving TS serum containing high levels of antineuronal and antinuclear antibodies. However, a third laboratory was unable to replicate these findings (Loiselle et al., 2003).

2. Relevance to Tourette Syndrome

In light of the contradictory findings obtained with the autoimmune model, investigators cannot draw any conclusions yet regarding its value as an animal model of TS. However, it has been shown that therapies directed toward reducing circulating autoantibody levels in PANDAS patients provide symptom relief (Perlmutter et al., 1999). These clinical findings emphasize the need to develop experimental models in order to identify the components of the immune response that are responsible for generating tic behavior in susceptible children.


This work was supported by the National Association of Research on Schizophrenia and Depression (NARSAD), and the National Institutes of Health grants MH049351, MH01527, MH52711 (PJL). We thank Dr. Surojit Paul for helpful comments on the manuscript.

Video Legends


segment 2 5 minutes after amphetamine injection.

segment 3 11 minutes after amphetamine injection.

segment 4 15 minutes after amphetamine injection.

segment 5 25 minutes after amphetamine injection.

Typical oral stereotypes associated with the psychostimulant model segment 6 Head up sniffing.

segment 7 Head down sniffing.

segment 8 Nose poking.

segment 9 Nose poking with biting.

segment 10 Licking.

Another feature of the psychostimulant model segment 11 Rat ignores novel object.


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