Mouse Models of Dystonia

C H A P T E R

27

Mouse Models of Dystonia Ellen J. Hess1, 2, H.A. Jinnah2, 3 1Department

of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA; 2Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; 3Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

O U T L I N E 27.1 Introduction

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27.2  Genetic Models of Dystonia 27.2.1  Dystonia Musculorum

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27.2.1.1 Background 27.2.1.2 Motor Disorder 27.2.1.3 Comment

27.3.1 Dystonia Induced by Cerebellar AMPA Receptor Activation 27.3.1.1 Background 27.3.1.2  Motor Disorder 27.3.1.3 Pathophysiology 27.3.1.4 Comment

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27.2.3  Scn8a Mutants 27.2.3.1 Background 27.2.3.2  Motor Disorder (as Reported) 27.2.3.3 Pathophysiology 27.2.3.4 Comment

27.3.2.1 Background 27.3.2.2  Motor Disorder (as Reported) 27.3.2.3 Comment

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27.2.6  Additional Genetic Models 27.3 Drug-Induced Models of Dystonia

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475 475 475 475 475

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27.4  Summary and Conclusions

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References476

27.1 INTRODUCTION Dystonia, the third most common movement disorder after tremor and Parkinson disease, is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures (Fahn and Marsden,

Movement Disorders, Second Edition http://dx.doi.org/10.1016/B978-0-12-405195-9.00027-5

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27.3.3.1 Background 27.3.3.2  Motor Disorder 27.3.3.3 Pathophysiology 27.3.3.4 Comment 27.3.4.1 Background 27.3.4.2  Motor Disorder 27.3.4.3 Pathophysiology 27.3.4.4 Comment

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27.3.3 Dystonia Caused by L-Type Calcium Channel Activation

27.3.4  Dystonia Caused by Infusion of Ouabain

27.2.4  Fibroblast Growth Factor 14-Deficient Mice 471 27.2.5  Wriggle Mouse Sagami 471 27.2.5.1 Background 27.2.5.2  Motor Disorder (as Reported) 27.2.5.3 Comment

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27.3.2 Systemic 3-Nitropropionic Acid Intoxification474

27.2.2 Cav2.1 (P/Q-type) Calcium Channel Mutants: Tottering, Leaner, and Knockouts 467 27.2.2.1  Leaner Mice 27.2.2.2  α1A Knockouts 27.2.2.3  Tottering Mice 27.2.2.4 Comment

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1994; Jankovic and Fahn, 1998). Dystonia is a heterogeneous disorder classified by the distribution of affected muscle groups. Focal or segmental forms of the disorder involve a small number of muscles, such as those of the hand in writer’s cramp or of the neck in torticollis. Generalized dystonia is characterized by involvement

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© 2015 Elsevier Inc. All rights reserved.

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27.  MOUSE MODELS OF DYSTONIA

of muscles throughout the body. The causes of dystonia are also heterogeneous. Dystonia may arise as a result of brain injury (Frei et al., 2004; Krauss and Jankovic, 2002; Lo et al., 2005) or occur as a sporadic (idiopathic) or inherited disorder (Schwarz and Bressman, 2009; Tanabe et al., 2009). The vast majority of cases are idiopathic. Because the biological basis of dystonia is not well understood, animal models have been used to provide insight into the biologic mechanisms underlying this movement disorder. Dystonia can be observed in mice (Messer and Strominger, 1980), rats (Lorden et al., 1988), and hamsters (Richter and Loscher, 1998). The dystonic rat model is described elsewhere in this volume. The dystonia exhibited by the rat model is chronic, abating only when the animal is at rest, whereas the hamster exhibits episodic periods of dystonia. Functional neuroanatomical mapping studies of the hamster model have revealed abnormalities in the basal ganglia (Richter and Loscher, 1998). Both the rat (LeDoux et al., 1993) and hamster models (Richter and Loscher, 1998) have also clearly implicated the cerebellum and related regions such as the red nucleus and thalamus in the phenotype. These animal models have provided significant insight into the neuroanatomical regions involved in dystonia. There are numerous mouse models of dystonia. Like the expression of dystonia in humans, the expression and etiology of dystonia in mice is heterogeneous. Dystonia in mice may arise as an inherited disorder or may be acquired through experimental manipulation. Therefore, mouse models have been used extensively to investigate the pathophysiology of dystonia.

27.2  GENETIC MODELS OF DYSTONIA 27.2.1  Dystonia Musculorum 27.2.1.1 Background This mutant emerged spontaneously at the Institute of Animal Genetics in Edinburgh and was first described in 1963 (Duchen et al., 1963). The mutation later proved allelic with the athetoid mutant (dtJ), which had arisen at least three times at the Jackson Laboratories in Bar Harbor, ME (Duchen, 1976). Several additional alleles have emerged independently in other mouse colonies, including one in Albany, NY (dtAlb) and another (dtOrl) in Orleans La Source, France (Messer and Strominger, 1980; Sotelo and Guenet, 1988). Dystonia musculorum mice carry a mutation in Bpag1, which encodes a neural isoform of the human bullous pemphigoid antigen (Brown et al., 1995, 1994; Pool et al., 2005). The protein plays a role in anchoring and stabilizing the cytoskeletal network within neurons (Dalpe et al., 1998; Yang et al., 1999) and also contributes

to function of the endoplasmic reticulum (Young and Kothary, 2008; Ryan et al., 2012). The mutation causes loss of neuronal cytoskeletal organization (Dalpe et al., 1998; De Repentigny et al., 2003), axonal swelling (Janota, 1972; Duchen et al., 1964), and abnormal axonal transport (De Repentigny et al., 2003) that culminates in axonal degeneration of primary sensory, motor, and autonomic neurons (Duchen et al., 1964, 1963; Sotelo and Guenet, 1988; Janota, 1972; Duchen, 1976; Guo et al., 1995; Kothary et al., 1988; Tseng et al., 2011; De Repentigny et al., 2011). Additionally, postnatal degeneration of muscle spindles that correlates with the onset of the motor disorder is observed, but skeletal muscle appears normal (Dowling et al., 1997). Bpag1 mRNA expression is actually much broader than that predicted by the histopathology (Dowling et al., 1997), suggesting that not all neurons are dependent on BPAG1 for cytoskeletal maintenance. BPAG1 is expressed in pontine, olivary, and sensory neurons that degenerate, but BPAG1 is also expressed in optic nerve, olfactory nerve, and sympathetic ganglia, which do not degenerate. Little or no BPAG1 is expressed in basal ganglia, cerebellum, or postnatal motor neurons, although lesions were noted in the striatum of dystonia musculorum mice (Messer and Strominger, 1980). These mutants also exhibit abnormal myelination in both the peripheral and central nervous system (Saulnier et al., 2002; Bernier and Kothary, 1998). At this time, the mechanisms by which dysfunction of the protein and subsequent pathology cause motor dysfunction are unknown. All strains were reported to have a similar motor phenotype with features resembling torsion dystonia in humans (Duchen et al., 1964; Messer and Strominger, 1980; Messer and Gordon, 1979; Richter and Loscher, 1998). Their writhing and twisting movements with muscle “spasms” leading to abnormal limb postures and severe difficulty with ambulation are carefully described in many previous reports (Messer and Gordon, 1979; Sotelo and Guenet, 1988; Messer and Strominger, 1980; Lalonde et al., 1994). However, the possibility of a severe sensory ataxia was raised by neuropathologic studies demonstrating relatively circumscribed lesions of sensory nerves and ganglia, cerebellum, and red nucleus (Duchen et al., 1964). Some reports therefore describe the animals as ataxic (Janota, 1972; Sotelo and Guenet, 1988; Brown et al., 1995), but most agree the motor syndrome is phenomenologically more consistent with generalized dystonia (Duchen et al., 1964; Messer and Strominger, 1980; Messer and Gordon, 1979; Richter and Loscher, 1998). 27.2.1.2  Motor Disorder (Video Segment 1) At rest, the dystonia musculorum mutants appear physically normal. Proximal movements, such as those of the shoulder or hip, are moderately abnormal. More

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27.2  Genetic Models of Dystonia

distal movements, such as those of the elbow or knee joints, seem most abnormal. The main abnormality is stiff, twisting, and poorly controlled movements. Many movements are slow and hesitant, though others are relatively quick and fluid. The poor limb control leads to impairments in ambulation. The limbs often take abnormal trajectories during stepping, such as the hind foot retracting above the spine. Because of the difficulty with limb control, the mice often ambulate with a swimming technique, in which they lie on the floor and use their limbs to paddle forward. At other times, they ambulate using an inchworm method, where the truncal muscles propel the head and shoulders forward with both forelimbs reaching out. After placing the forelimbs down, the mice draw the hind limbs in toward the body. Due to the impaired ambulation, the animals spend a significant proportion of time resting motionless, typically with the head and abdomen lying on the floor, the forelimbs folded back along the trunk, and the hind limbs extended caudally. Falling is infrequent, since the animals maintain a widened stance with a low center of gravity, and they rarely rear onto the hind limbs. After a fall, there is an obvious delay in regaining the upright posture because of the axial twisting and poor motor control. Supplementary data related to this chapter can be found at http://dx.doi.org/10.1016/B978-0-12-4051959.00027-5 27.2.1.3 Comment This mutant demonstrates that a motor syndrome closely resembling generalized torsion dystonia in humans can occur in the mouse. Overall, the majority of abnormal movements are best characterized as dystonic, though some of the movements might also be considered choreic because they are more rapid and fluid. Though generalized, there is an anatomic gradient of involvement, with distal muscles more severely affected than proximal muscles.

27.2.2 Cav2.1 (P/Q-type) Calcium Channel Mutants: Tottering, Leaner, and Knockouts The Cacna1a gene encodes the α1A pore-forming subunit of the high voltage-gated P/Q-type calcium channel. Calcium channels are composed of five subunits (α1, α2, β, δ, and γ); however, the α1 subunit alone is sufficient to form the structural channel and confer voltage sensitivity. These channels are characterized by voltage-sensitive activation in response to depolarization, resulting in the selective increase in calcium flux into the cell. CACNA1A defects in humans were first associated with episodic ataxia type 2, familial hemiplegic migraine, and spinocerebellar ataxia type 6; dystonia is increasingly recognized as a salient feature of these disorders

467

(Cuenca-Leon et al., 2009; Arpa et al., 1999; Jen et al., 2007). Further, some patients with CACNA1A mutations exhibit only dystonia (Sethi and Jankovic, 2002; Giffin et al., 2002; Spacey et al., 2005; Cuenca-Leon et al., 2009; Roubertie et al., 2008). There are currently at least five mouse models carrying mutations in the Cacna1a gene that exhibit dystonia: tottering (Cacna1atg), leaner (Cacna1atg-la), rocker (Cacna1atg-rk), and two Cacna1a knockout mice. 27.2.2.1  Leaner Mice 27.2.2.1.1 BACKGROUND

The leaner mutation arose spontaneously at the Jackson Laboratories (Yoon, 1969). The leaner mutation causes a gross disruption in the α1A subunit protein, resulting from a G to A point mutation of a splice donor site near the 3′ end of the gene (Fletcher et al., 1996; Doyle et al., 1997). The mutation produces aberrantly spliced mRNA resulting in a premature stop codon. Further, mutant mRNA expression is quite low, possibly due to nonsense-mediated decay (Veneziano et al., 2011). 27.2.2.1.2  MOTOR DISORDER (VIDEO SEGMENT 2)

In leaner mice, the dystonia is chronic and extreme, with episodes of increased severity that are barely detectable over the background motor dysfunction. Historically, leaner mice have been characterized as ataxic (Meier and MacPike, 1971; Herrup and Wilczynski, 1982; Tsuji and Meier, 1971; Yoon, 1969; Rhyu et al., 1999; Heckroth and Abbott, 1994), which suggests falling due to disturbances in balance. However, when the term ataxia is applied to mice, it is often used as a nonspecific descriptor that encompasses a wide range of gait disturbances. Leaner mice have an extremely debilitating gait abnormality starting at approximately postnatal day 18, resulting from their severe and chronic dystonia. In fact, leaner mice do not fall because they are ataxic; rather, they are propelled onto their flanks because the severe dystonia results in stiff extension of the limbs on one side as they attempt to walk. After falling, there is a considerable delay in gaining the upright posture. Limb tone is increased, with a marked reduction in spontaneous activity and extremely slow and stiff movements. The dystonia is generalized, with involvement of proximal and distal muscles, including the jaw and tongue. Leaner mice do not generally survive past weaning because the severe dystonia limits their ability to obtain and consume both food and water. However, if leaner mice are provided with softened chow and hydration is maintained, these mice can live a normal life span and even breed. As leaner mice age, the dystonia wanes but never entirely remits. Supplementary data related to this chapter can be found at http://dx.doi.org/10.1016/B978-0-12-405195-9. 00027-5.

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467.e1

The following are the supplementary data related to this chapter:

The following are the supplementary data related to this chapter:

Video Segment 1 Dystonia musculorum mouse. This video demonstrates the typical resting posture, the characteristic stiff and twisting dystonic movements, and the peculiar strategy for ambulation.

Video Segment 2 Leaner mouse. This clip demonstrates reduced spontaneous mobility with extremely slow and stiff twisting movements of the trunk and limbs, suggestive of dystonia superimposed upon a hypokinetic motor syndrome.

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27.  MOUSE MODELS OF DYSTONIA

27.2.2.1.3 PATHOPHYSIOLOGY

Neuropathologic surveys demonstrate relatively circumscribed degenerative changes of the cerebellum (Herrup and Wilczynski, 1982; Heckroth and Abbott, 1994). These studies have revealed widespread degeneration of cerebellar granule, Purkinje, and Golgi cells that is most prominent anteromedially (Meier and MacPike, 1971; Herrup and Wilczynski, 1982). The degenerative process is most severe during the first few months of age, but continues throughout adulthood, leaving less than 20% of Purkinje cells by 1 year of age. The surviving Purkinje cells ectopically express tyrosine hydroxylase, an enzyme normally associated with catecholaminergic cells (Hess and Wilson, 1991; Abbott et al., 1996). Whole-cell recording of leaner mutant Purkinje cells reveals an overall reduction in Cav2.1 calcium current density (Dove et al., 1998; Lorenzon et al., 1998). Cellattached patch recordings demonstrated a reduction in open probability of leaner channels, explaining the reduction in current density (Dove et al., 1998). It is not yet clear how or if these abnormalities are associated with dystonia. The leaner mutation results in a reduction in acetylcholine release at neuromuscular synapses and a reduction in cerebellar parallel fiber-evoked excitatory postsynaptic potentials (Kaja et al., 2007, 2008; Liu and Friel, 2008), which is not surprising, as Cav2.1 channels play an important role in neurotransmitter release. However, because other voltage-gated calcium channels appear to, in part, compensate for the reduction in Cav2.1 current (Kaja et al., 2007; Etheredge et al., 2007), the phenotype is not likely explained by a simple across-the-board reduction in neurotransmitter release. 27.2.2.2  α1A Knockouts 27.2.2.2.1 BACKGROUND

Two strains of Cacna1a knockout mice were generated by targeted disruption (Fletcher et al., 2001; Jun et al., 1999), resulting in the elimination of the α1A subunit protein and the P/Q-type calcium channel current (Fletcher et al., 2001; Jun et al., 1999; Aldea et al., 2002). The neuropathology in these mice is very similar to leaner mice with late-onset progressive degeneration of the anterior cerebellum (Fletcher et al., 2001). 27.2.2.2.2  MOTOR DISORDER (AS OBSERVED BY THE AUTHORS)

Juvenile Cacna1a-null mutants exhibit a motor disorder similar to that of juvenile leaner mutants, with some minor differences. In comparison to leaner mutants, the Cacna1a-null mutants are much smaller throughout development, have more profound motor impairments, and display much less spontaneous activity. They almost uniformly perish at 3–4 weeks of age when the transition from suckling to eating solid food occurs in normal mice. With daily parenteral hydration and nutrition, a very

small percentage of α1A-null mutants survive to adulthood. The adult Cacna1a-null mutants again resemble the adult leaner mice, but they have more severe motor impairments, characterized by akinesia, bradykinesia, stiff movements, and increased muscle tone. They are unable to eat and drink on their own, requiring daily parenteral supplementation for survival. The motor disorder of the Cacna1a knockouts, like that of leaner mice, is most consistent with generalized dystonia. 27.2.2.2.3 PATHOPHYSIOLOGY

An increase in the expression of N-type and L-type calcium channels is observed in the null mutants (Fletcher et al., 2001; Jun et al., 1999; Aldea et al., 2002; Pagani et al., 2004). This abnormality in calcium handling may play a role in the dystonia as described below in the pathophysiology section for tottering mice. 27.2.2.3  Tottering Mice 27.2.2.3.1 BACKGROUND

Tottering is a spontaneously occurring autosomal recessive mutation. The tottering missense mutation is located in the pore-forming domain of the P/Q-type calcium channel (Fletcher et al., 1996). Surprisingly, channel properties of tottering mice reveal only subtle changes, with a slight increase in the noninactivating component of voltage-dependent inactivation (Wakamori et al., 1998) but an approximate 40% reduction in whole cell calcium current density. Though few gross neuropathologic abnormalities can be identified in Nissl-stained material from the tottering brain (Green and Sidman, 1962; Levitt, 1988; Noebels and Sidman, 1979), quantitative measures demonstrate subtle decreases in brain volume and the size of cerebellar Purkinje cells (Isaacs and Abbott, 1995). Electron microscopic and Golgi-impregnated material reveal few abnormalities, except for shrunken cerebellar Purkinje cells, abnormal Purkinje cell connectivity, and diffuse axonal swellings or torpedoes in older mice (Meier and MacPike, 1971; Rhyu et al., 1999). In addition, catecholaminergic measures appear abnormal. There is apparent hyperinnervation of multiple brain regions by noradrenergic fibers, with an associated increase in tissue norepinephrine content (Levitt and Noebels, 1981; Noebels, 1984). In addition, tyrosine hydroxylase is ectopically expressed in cerebellar Purkinje cells, with relatively normal patterns of expression in the midbrain and locus coeruleus (Hess and Wilson, 1991; Abbott et al., 1996; Heckroth and Abbott, 1994; Fletcher et al., 1996). The initial report of the motor disorder described a mild baseline ataxia with intermittent attacks of more profound motor dysfunction that were originally thought to represent motor seizures (Green and Sidman, 1962). However, subsequent electroencephalography studies failed to identify any abnormal

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27.2  Genetic Models of Dystonia

activity consistently associated with the motor attacks, questioning the classification of the intermittent attacks as epileptic seizures (Kaplan et al., 1979; Noebels and Sidman, 1979). Instead, several of these studies describe 6  Hz polyspike discharges in association with brief periods of behavioral inactivity suggestive of absence seizures (Kaplan et al., 1979; Noebels and Sidman, 1979; Heller et al., 1983). Although the tottering mice exhibit a motor disorder that was originally classified as epilepsy, recent studies suggest that the motor disorder is better described as paroxysmal dystonia. 27.2.2.3.2  MOTOR DISORDER (VIDEO SEGMENT 3)

Tottering mouse motor attacks are highly stereotyped. The start of an attack is nearly always signaled by the extension of the hind limbs. This initial phase is followed by abduction at the hip and extension at the knee, ankle, and paw, with a stiffly arched back, which presses the perineum against the cage bottom. The motor dysfunction then spreads to involve the forelimbs and head, with severe flexion of the neck. During this time, mice assume and maintain twisted and abnormal postures involving the entire body. In the final phase, the mice regain control of the hind limbs, often rearing, while forepaws and facial muscles continue to contract (Green and Sidman, 1962). The entire episode lasts 30–60 min without loss of consciousness. Supplementary data related to this chapter can be found at http://dx.doi.org/10.1016/B978-0-12-405195900027-5. Movement disorders in humans are sometimes difficult to classify. This problem is even more difficult in mice, where normal and abnormal motor behaviors are not well studied. As a result, motor abnormalities in mice are often mislabeled or vaguely classified. Although the tottering mouse motor phenotype has been described as myoclonus, convulsions, focal motor seizures, or Jacksonian march, the episodic motor events in tottering mice are better characterized as paroxysmal dystonia rather than epilepsy for several reasons. First, the observed phenomenology, with sustained and asynchronous twisting postures, is more characteristic of dystonia than motor seizures. Second, the duration of 30–60 min is consistent with dystonia, but quite unusual for a seizure, which typically lasts for only 1–60 s. Third, despite apparent generalization with involvement of the entire trunk and all limbs, the motor abnormalities are not associated with epileptiform activity on the electroencephalogram (EEG) (Kaplan et al., 1979; Noebels and Sidman, 1979). Fourth, based on multichannel electromyography (EMG), the characteristics of the abnormal movements are consistent with dystonia in humans (Scholle et al., 2010; Raike et al., 2012).

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27.2.2.3.3 PATHOPHYSIOLOGY

The gene defect(s) in the Cacnala mutants predicts that abnormalities in calcium handling likely play a role in the mutant phenotype. In fact, it appears that calcium channel expression is abnormal in these mutants. A compensatory increase in the expression of N-type and L-type calcium channels is observed in both the Cacnala knockout mice and tottering mice (Fletcher et al., 2001; Jun et al., 1999; Aldea et al., 2002; Pagani et al., 2004; Campbell and Hess, 1999; Qian and Noebels, 2000; Zhou et al., 2003; Erickson et al., 2007). Consistent with these findings, drugs that block L-type calcium channels block the paroxysmal dystonia in tottering mutant mice (Campbell and Hess, 1999). Conversely, L-type calcium channel agonists induce dystonia in tottering mice (Campbell and Hess, 1999). This suggests that an upregulation in the L-type calcium channel subtype, which appears to be a secondary effect of the mutated P/Q-type calcium channel, contributes to the expression of the dystonia in tottering mice. In tottering mice, the neuroanatomical substrates of the dystonic events were identified using markers of cell activity, such as the immediate early transcription factor c-fos. During a dystonic attack, cerebellar neurons are activated, including granule cells and Purkinje cells. Further, medial vestibular nuclei, deep cerebellar nuclei, red nuclei, inferior olivary complex, and ventrolateral thalamic nuclei, which are principal relay components of cerebellar circuitry, are also activated. Dystonic events do not induce c-fos expression in the basal ganglia, a region involved in motor control and traditionally associated with dystonia. These findings clearly implicate the cerebellum and related nuclei in the dystonia (Campbell and Hess, 1998). The cerebellum was again implicated in the expression of the tottering mouse dystonia through lesion studies. Surgical removal of the cerebellum eliminates dystonia in tottering mice (Neychev et al., 2008). Further, selective destruction of Purkinje cells through the use of specifically expressed toxic transgenes or mutations in the tottering mouse ameliorates the dystonic movements (Campbell et al., 1999; Raike et al., 2012), suggesting that Purkinje cell dysfunction is critical in mediating the dystonic phenotype. To determine whether cerebellar dysfunction alone could cause dystonia, the dystonia-causing tottering gene defect was isolated to Purkinje cells through the use of conditional genetic manipulation, whereas neurons elsewhere in the brain were not affected (Raike et al., 2012). Mice with defects restricted to Purkinje cells exhibited dystonic movements, demonstrating that abnormal Purkinje cells alone are sufficient to generate dystonic movements. Although the cerebellum may instigate the dystonia, other brain regions also play a role as mild striatal lesions exacerbate the severity of the dystonia (Neychev et al., 2008).

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27.2  Genetic Models of Dystonia

The following are the supplementary data related to this chapter:

Video Segment 3 Tottering mouse. These clips show the ataxic and tremulous baseline ambulation followed by the characteristic attack that typically proceeds in a caudal-to-rostral direction.

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The dystonic movements in tottering mice are also associated with abnormal Purkinje cell activity (Chen et al., 2009; Walter et al., 2006) and low-frequency oscillations in the cerebellar cortex, a phenomenon that is not observed in normal mice. These oscillations are accompanied by increasingly coherent oscillations in electromyographic activity in the face and hind limb during abnormal movements (Chen et al., 2009), providing strong support for an association between dystonic movements and aberrant activity in the cerebellum.

background, the phenotype is nearly identical to the severe lethal phenotype of med mice. However, on a mixed strain background (C57BL/6J X C3H), many medJ mice survive to adulthood and display a phenotype with features resembling dystonia. The enhanced survival is due to the presence of an auxiliary spliceosomal protein (SCM1) in the C3H mouse strain that doubles the percentage of correctly spliced transcripts; in C57BL/6J mice, this splice factor is mutated, rendering it nonfunctional (Buchner et al., 2003; Howell et al., 2007).

27.2.2.4 Comment These findings suggest that the cerebellum is involved in the expression of dystonia in these mutants. Although the cerebellum itself does not directly produce or initiate movements, these results suggest that the abnormal signal can ultimately influence the expression of the motor component of these episodes. This notion is concordant with the rat (Lorden et al., 1988) and hamster (Richter and Loscher, 1998) models of dystonia and with functional imaging in humans (Argyelan et al., 2009; CeballosBaumann et al., 1997; Carbon et al., 2008; Odergren et al., 1998; Preibisch et al., 2001; Ceballos-Baumann et al., 1995; Kluge et al., 1998), where the cerebellum is also implicated.

27.2.3.2  Motor Disorder (as Reported) Adult medJ mice on a mixed-strain background (C57BL/6J X C3H) exhibit movement-induced tremor of the head and dystonic posturing. Abnormal twisting postures of the trunk and repetitive movements of the limbs are sustained over the course of seconds to minutes (Messer and Gordon, 1979; Hamann et al., 2003). Mice are not able to ambulate with a coordinated gait due to the persistence of the twisting and posturing. The abnormal movements of the extremities abate with sleep, but axial torsions persist. These mice also exhibit severe muscle weakness and reduced muscle mass (Hamann et al., 2003; Sprunger et al., 1999; Kearney et al., 2002). The profound movement disorder reduces spontaneous locomotor activity. The EEG is normal in these mice, ruling out a possible seizure disorder in medJ mice, although spike-wave discharges are observed in heterozyous med and medjo mice (Papale et al., 2009). In contrast to most other dystonias, the movement disorder of medJ mice can be suppressed with phenytoin, a sodium channel blocker (Hamann et al., 2003).

27.2.3  Scn8a Mutants 27.2.3.1 Background Several mutations have been identified at the mouse locus “motor endplate disease” (med), which encodes the gene Scn8a, the Nav1.6 sodium channel expressed throughout the nervous system (Burgess et al., 1995). The med mouse mutant arose from an insertion of a truncated LINE element into exon 2 of Scn8a, causing abnormal splicing of exon 1 to an acceptor site within intron 2 and a frame shift that reads a premature stop codon in exon 3 (Kohrman et al., 1996a). These mice are essentially null mutants and exhibit severe neurological impairment including paralysis, progressive muscle atrophy, and death within the first month (Duchen et al., 1967). The allelic mouse mutant jolting (medjo) is caused by a point mutation that replaces the Ala with Thr at residue 1071 (Kohrman et al., 1996b). This mutation results in a small shift in voltage-dependent activation of the channel (Kohrman et al., 1996b) and a relatively mild phenotype consisting of widened stance, unsteady gait, and tremor of the head and neck (Dick et al., 1985). The mouse mutant medJ carries a four base pair deletion within the 5′ splice donor site of exon 3 causing aberrant splicing from exon 1 to exon 4 (Kohrman et al., 1996a). Most Scn8a mRNA produced in these mutants is abnormally spliced, but a small percentage of transcript is correctly spliced, resulting in very low expression of the protein (Sprunger et al., 1999; Kearney et al., 2002). When the medJ mutation is expressed on a C57BL/6J

27.2.3.3 Pathophysiology Many of the physiological studies have focused on the med and medjo alleles. There are clear abnormalities in neuromuscular transmission in med mice, which do not express the Nav1.6 sodium channel. The weakness in these mice results from a failure of evoked transmitter release from motor nerves; this likely causes the loss of muscle mass (Harris and Pollard, 1986). A similar defect likely accounts for the weakness observed in medJ mice. Because the medjo mice are ataxic, Purkinje cell firing rates were examined in med and medjo and Purkinje cellspecific knockout mice. In all mutants, there is a striking reduction in Purkinje cell simple spike firing (Harris et al., 1992; Dick et al., 1985; Raman et al., 1997; Levin et al., 2006). Similar defects occur in cerebellar granule cells, cortical pyramidal neurons, neurons of the dorsal cochlear nucleus, and spinal motor neurons (Chen et al., 1999; Garcia et al., 1998; Maurice et al., 2001; Van Wart and Matthews, 2006; Osorio et al., 2010). Further, Nav1.6 sodium channels also mediate pacemaking and fast spiking in globus pallidus neurons (Mercer et al., 2007), suggesting that the phenomenon is not specific to Purkinje cells.

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27.2  Genetic Models of Dystonia

27.2.3.4 Comment medJ mice exhibit a movement disorder very similar to generalized dystonia, but some elements of the phenotype are uncharacteristic of dystonia. Generally, dystonia in humans abates with sleep (McGeer and McGeer, 1988), whereas the medJ mice maintain twisted postures; interestingly, sleep patterns are disrupted in medjo mice (Papale et al., 2010), which may, in part, explain the sustained abnormal postures during sleep. The muscle weakness in these mice is also not common in dystonia. Overall, the mice appear to be dystonic with some atypical features. EMG, which generally reveals cocontraction of agonist and antagonist muscles in dystonia, may help to clarify the nature of the movement disorder.

27.2.4  Fibroblast Growth Factor 14-Deficient Mice Spinocerebellar ataxia type 27, which is characterized by tremor, ataxia, and dyskinesias, is associated with a mutation in FGF14 (van Swieten et al., 2003). Mice deficient in fibroblast growth factor 14 (FGF14) similarly exhibit tremor, ataxia, and paroxysmal dystonia. FGF14 is expressed in the developing and adult nervous system. In adults, FGF14 mRNA is expressed at high levels in the basal ganglia and cerebellum, with lower levels in the hippocampus and cortex (Wang et al., 2002). FGF14-deficient mice develop normally and have an intact nervous system. However, these mice are subsensitive to dopamine agonists, suggesting abnormalities of the basal ganglia and consistent with the pattern of mRNA expression (Wang et al., 2002). Further, Purkinje cell firing rates are attenuated in FGF12-deficient mice, suggesting abnormalities of the cerebellum (Shakkottai et al., 2009). These mice are described as ataxic, with a widened stance and abnormal gait. In addition, paroxysmal dyskinesia is observed in the younger mutants. Episodes of limb extensions with involuntary rearing and twisting that cause the mice to topple over occur several times a day and last for 7–12 min (Wang et al., 2002). These episodes do not appear to be seizures, as no abnormalities were detected with EEG. A video of the paroxysmal dyskinesia exhibited by the FGF14-deficient mice can be viewed at http://www.neuron.org/cgi/ content/full/35/1/25/DC1/. These mice are notable because FGF14 mediates axonal targeting and the functional properties of Nav1.6 sodium channels, suggesting a functional link between the phenotypes of the medJ mice and FGF14-deficient mice (Laezza et al., 2009). Further, FGF14-deficient mice implicate dysfunction of several brain regions, including the basal ganglia, cortex, and cerebellum, in the motor disorder.

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27.2.5  Wriggle Mouse Sagami 27.2.5.1 Background The mouse mutant known as wriggle mouse sagami (wri) arose spontaneously at the Ohmura Institute for Laboratory Animals in Japan. The mutation in wriggle mouse sagami was identified as a point mutation the Pmca2 gene, a plasma membrane Ca2+-ATPase (Takahashi and Kitamura, 1999). This mutation is allelic with deafwaddler (dfw), a mutant that has been studied as a model of deafness and vestibular disorders. In fact, stereocilia of the cochlea are completely absent in wriggle mouse sagami (Takahashi and Kitamura, 1999), the cochlea and saccule degenerate, and the mice are completely deaf at 1 month of age (Takahashi et al., 1999). There are no gross changes within the nervous system itself, but closer inspection reveals a decrease in the number of parallel fiber–Purkinje cell contacts and an increase in “bouton-like” structures of Purkinje cells (Inoue et al., 1993). Additionally, the levels of several neurotransmitters are altered in these mutants; norepinephrine and serotonin are increased (Ishikawa et al., 1989; Kumazawa et al., 1989), while GABA is increased only in the striatum (Ikeda et al., 1989). The increase in the monoamines may contribute to the motor abnormalities as ritanserin, a serotonergic antagonist, and prazosin, a noradrenergic antagonist, reduce the motor signs (Ikeda et al., 1989). 27.2.5.2  Motor Disorder (as Reported) Wriggle mouse sagami exhibits a complex motor disorder characterized by jerky movements of the head and neck, occasional limb abduction, and frequent rolling of the trunk, which makes it difficult for the mice to remain upright and to obtain food and water (Ikeda et al., 1989). These mice do not exhibit seizures, nor are they weak; tone appears to be increased. Although the movements abate with sleep, the mice maintain an abnormal posture while sleeping, which is atypical of dystonia. 27.2.5.3 Comment Although wriggle mouse sagami has been presented as a dystonic mouse mutant, the presence of additional abnormalities such as vestibular defects suggests that dystonia is only a minor component of a more complex phenotype. Since vestibular defects alone may induce a variety of abnormal movements, the use of these mice as a model for dystonia must be interpreted with caution.

27.2.6  Additional Genetic Models Many strains of engineered mice carry mutations in genes known to cause dystonia in humans. These genetic models have etiologic validity, but surprisingly few of these models have face validity. That is, none of the genetic models, with the exception of the α-synuclein and Pnkd mutants, exhibit dystonia, although most exhibit some kind of motor dysfunction (Table 27.1).

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TABLE 27.1  Other Genotypic Models Gene

Protein

Human Disease

Mouse Motor Phenotype

Citations

ARSA

Arylsulfatase A

Metachromatic leukodystrophy

Abnormal rotarod performance and progressive ataxia

D’Hooge et al. (2001)

ATM

ATM

Ataxia telangiectasia

Supersensitive to amphetamine; stride length asymmetry

Eilam et al. (1998)

ATP1A3

Na+/K+-ATPase (α3 subunit)

Rapid-onset dystonia with parkinsonism (DYT12)

Enhanced locomotor response to methamphetamine; seizures; in females, abnormal performance on rotarod, beam walking, and wheel running in response to stress

DeAndrade et al. (2011), Moseley et al. (2007), Clapcote et al. (2009)

ATP7B

Copper ATPase

Wilson disease

None reported

Buiakova et al. (1999)

GCDH

Glutaryl-CoA dehydrogenase

Glutaric acidemia

Abnormal performance on rotarod, beam Koeller et al. (2002) walking, and prepulse inhibition

GCH1

GTP cyclohydrolase

DOPA-responsive dystonia

Normal behavior with wasting syndrome Bode et al. (1988) after phenylalanine challenge

NPC1

NPC1 (endosomal cholesterol transporter)

Niemann-Pick type C

Hypoactivity, abnormal habituation, poor Voikar et al. (2002), Morris coordination, tremor, abnormal gait et al. (1982)

HPRT

Hypoxanthine phosphoribosyl transferase

Lesch-Nyhan disease

Normal behavior but supersensitive to amphetamine

Jinnah et al. (1991)

HTT

Huntington

Huntington disease

Strain-dependent; hyperactivity, repetitive behaviors, cognitive deficits, late-stage akinesia, aggressive behavior

Menalled et al. (2002), Shelbourne et al. (1999), Reddy et al. (1998), Nasir et al. (1995)

MJD1

Ataxin-3

Machado-Joseph disease (SCA3)

Gait abnormalities, hypotonia, tremor, hypoactivity

Cemal et al. (2002), Ikeda et al. (1996)

PANK2

Pantothenate kinase 2

Pantothenate kinase-associated neurodegeneration (PKAN, formerly HallervordenSpatz syndrome)

None noted

Kuo et al. (2005)

PARK2

Parkin

Parkinson disease

Impaired beam walking and somatosensory function

Goldberg et al. (2003)

PLP1

Proteolipid protein

Pelizaeus-Merzbacher disease

Tremor, seizures

Meier and MacPike (1970), Eicher and Hoppe (1973)

PNKD

PNKD

Paroxysmal nondinesigenic dyskinesia

Paroxysmal oral-facial dyskinesias and stereotypies in response to stress, caffeine, and ethanol challenge

Lee et al. (2012)

PPT1

Palmitoyl protein thioesterase

Infantile neuronal ceroid lipofuscinosis

Spasticity, myoclonus, seizures

Gupta et al. (2001)

PTS

6-Pyruvoyltetrahydropterin synthase

DOPA-responsive dystonia

Abnormal performance on beam walking Sumi-Ichinose et al. (2001), Sato et al. (2008)

SGCE

Epsilon-sarcoglycan

Myoclonus-dystonia (DYT11)

Myoclonus; hyperactivity; abnormal performance on beam walking

Yokoi et al. (2006)

SNCA

α-synuclein

Parkinson disease

Rigidity, dystonia, hindlimb freezing, loss of righting reflex, paralysis

Lee et al. (2002), Giasson et al. (2002), Gomez-Isla et al. (2003)

TOR1A

TorsinA

DYT1 dystonia (Oppenheim Failure to feed in the knockouts; slowed dystonia) habituation in knockdowns; abnormal performance on beam walking

Dauer and Goodchild (2004), Dang et al. (2005)

TH

Tyrosine hydroxylase

DOPA-responsive dystonia

Althini et al. (2003)

Mild to marked hypoactivity

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27.3  Drug-Induced Models of Dystonia

The lack of a dystonic phenotype may be attributed to several causes. First, few models are an exact genocopy of the human mutation. Many of the mouse models were generated by spontaneous mutation, by chemically induced mutation, or by homologous recombination to produce null mutants (knockouts), and thus do not carry the exact mutation that causes the human disease. It is interesting to note that where dystonia is observed in the α-synuclein and Pnkd mutants, a transgene with the precise human point mutation was used to generate the mice (Lee et al., 2002; Gomez-Isla et al., 2003; Lee et al., 2012). In contrast, α-synuclein knockout mice, which are completely deficient in α-synuclein, do not display dystonia and have very mild phenotype (Cabin et al., 2002). Thus, the mutant protein itself may be an important factor in driving the dystonic phenotype, and a precise recapitulation of human mutations in mice may be necessary to reproduce the dystonia. Clearly, the generation of more knockin models will help to address this question. Alternatively, the lack of a dystonic phenotype in these genetic models may be attributed to speciesspecific effects. The mouse brain may be sufficiently different from humans to prevent the expression of dystonia, or mice may not live long enough to fully develop the disease with the accompanying dystonia. Obviously, species-specific attributes are impossible to avoid in genetic models, but this does not mean the models should be discarded and does not diminish the utility of the models. The genetic models have proven invaluable in understanding the molecular, cellular, and neuropathologic phenotypes underlying the genetic disorders.

27.3  DRUG-INDUCED MODELS OF DYSTONIA Genetic models of dystonia provide obvious parallels to human disease and are a rich source for understanding the pathophysiology of dystonia. However, all genetic models are fraught with the complications that accompany the development of the nervous system in the context of a mutation, including compensatory changes and cell death. In contrast, drug-induced models of dystonia provide a tool to understand the pathophysiology of dystonia on a background of normal neurological function. The etiology of the dystonia in these models may not directly reflect the etiology of the condition in humans, but this does not detract from the value of the model or the knowledge gained from the model. The real value of drug-induced models is that they may be useful in defining pathophysiological defects common to many forms of dystonia. Drug-induced models complement the genetic models, in that hypotheses derived from

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work in genetic models may be tested for their general applicability in the drug-induced models and vice versa.

27.3.1  Dystonia Induced by Cerebellar AMPA Receptor Activation 27.3.1.1 Background Abnormal cerebellar function is implicated in human dystonia (Argyelan et al., 2009; Ceballos-Baumann et al., 1997; Carbon et al., 2008; Odergren et al., 1998; Preibisch et al., 2001; Ceballos-Baumann et al., 1995; Kluge et al., 1998) as well as in dystonia in mice (Messer and Strominger, 1980; Campbell et al., 1999; Sprunger et al., 1999), rats (Lorden et al., 1988), and hamsters (Richter and Loscher, 1998). The accumulated evidence suggests that an increase in cerebellar activity is associated with dystonia in both humans and animals. Therefore, the cerebellum became an obvious target for the development of a drug-induced model of dystonia. 27.3.1.2  Motor Disorder (Video Segment 4) Low doses of the excitatory glutamate receptor agonist kainic acid microinjected into the mouse cerebellum produces dystonia in mice. Kainate microinjection results in the acute expression of gross generalized dystonia without cerebellar cell death and without inducing seizures (Pizoli et al., 2002). After kainate injection, mice display abnormal postures including a stiffly arched back, which presses the perineum against the cage bottom, while they exhibit a dystonic paddling motion of the hind limbs and sustained twisted abnormal postures that involve most of the body. With moderate doses of kainate, mice assume dystonic postures after being disturbed, and dystonia occurs with volitional movement. At higher doses of kainic acid, mice assume sustained abnormal postures for several minutes with involvement of the face and neck as well as the rest of the body. Supplementary data related to this chapter can be found at http://dx.doi.org/10.1016/B978-0-12-4051959.00027-5. 27.3.1.3 Pathophysiology Human functional imaging and lesion experiments in animal models suggest that cerebellar activation is likely involved in the expression of dystonia. However, in mice, cerebellar injections of agents that produce a nonspecific increase in cerebellar excitability, such as that produced by GABA receptor antagonists, potassium channel blockers, or sodium channel activators, is not sufficient to induce dystonia. Instead, AMPA receptor activation within the cerebellum evokes dystonia in both mice and rats (Alvarez-Fischer et al., 2012; Pizoli et al., 2002), but activation of other glutamate receptor subtypes such as kainate or NMDA receptors does not

III. DYSTONIA

27.3  Drug-Induced Models of Dystonia

The following are the supplementary data related to this chapter:

Video Segment 4 Kainate-induced dystonia. Each segment illustrates a typical dystonic posture after intracerebellar microinjection with 0.5 μl of 100 μg/ml kainic acid. Both the motor and temporal aspects of the dystonia in the video are representative of the model. A single mouse was used throughout the video including the recovery phase, which occurred 2 h after the injection. Note that the mouse returned to near-normal levels of locomotor activity.

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provoke dystonia (Fan et al., 2012). In addition, AMPA receptor desensitization mediates the severity of the dystonia, whereby the dystonic movements are more severe when desensitization is prevented. Microinjection of a glutamate agonist elsewhere in the brain does not cause dystonia, and mice lacking cerebellar Purkinje cells exhibit significantly less dystonia than intact mice (Pizoli et al., 2002). Further, cerebellar microinjection of a glutamatergic antagonist does not cause dystonia, suggesting that simply distorting glutamatergic cerebellar signaling is insufficient to produce dystonia (Pizoli et al., 2002; Fan et al., 2012). Rather, cerebellar excitation is necessary. Like tottering mice, although cerebellar insult clearly instigates the dystonia, other brain regions also play a role as mild striatal lesions exacerbate the severity of the dystonia (Neychev et al., 2008). 27.3.1.4 Comment This model demonstrates that dystonia can be provoked in an animal with a normal nervous system. That is, chronic changes in physiology or wiring, which may occur in genetic models, are not necessary to produce dystonia. The model also demonstrates that dystonia occurs with abnormal cerebellar activity, which predicts abnormal activity in the cerebellum in dystonic patients. Indeed, the cerebellum exhibits hypermetabolism that exceeds any other brain region in functional imaging of patients with dystonia (Argyelan et al., 2009; Ceballos-Baumann et al., 1997; Carbon et al., 2008; Odergren et al., 1998; Preibisch et al., 2001; CeballosBaumann et al., 1995; Kluge et al., 1998). Thus, it is possible that the cerebellar overactivity observed in neuroimaging studies of patients with dystonia is associated with abnormal glutamate signaling.

27.3.2  Systemic 3-Nitropropionic Acid Intoxification 27.3.2.1 Background 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of mitochondrial complex II. This toxin was first identified in China after ingestion of moldy sugarcane caused a movement disorder that includes dystonia and chorea (Liu et al., 1992). In fact, the basal ganglia appear to be especially sensitive to the effects of this toxin, given that systemically administered 3-NP causes selective lesions within the basal ganglia, but not elsewhere in brain. 3-NP intoxification is used as a model of Huntington disease in primates, rats, and, more recently, mice. Mice are relatively resistant to the effects of 3-NP, but Fernagut et al. (2002) demonstrated that an escalating dose regimen delivered to mice over the course of nearly 2 weeks results in cell death within the basal ganglia.

Although the dose regimen is lethal in one-third of mice, in surviving mice, circumscribed lesions occur in the dorsolateral striatum and cell loss is observed in the globus pallidus pars externalis, and in the substantia nigra pars reticulata and compacta. 27.3.2.2  Motor Disorder (as Reported) Histopathology in the basal ganglia is accompanied by a complex motor disorder, which varies in severity. Investigators describe a motor syndrome similar to the rat 3-NP model that includes motor slowing, hind limb dystonia, truncal dystonia, and impaired postural control (Fernagut et al., 2002). 27.3.2.3 Comment In contrast to kainate-induced dystonia, which directly implicates the cerebellum, this model clearly implicates the basal ganglia in dystonia in mice. Indeed, abnormalities of the basal ganglia are often observed in neuropathologic studies and neuroimaging of individuals with dystonia (Jankovic and Fahn, 1998). The kainate- and 3-NP-induced models suggest that the neuroanatomical underpinnings of dystonia are likely heterogeneous, much like the disorder itself.

27.3.3  Dystonia Caused by L-Type Calcium Channel Activation 27.3.3.1 Background Calcium channel agonists, particularly L-type calcium channels agonists, were good candidates for the development of a drug-induced model of dystonia for several reasons. First, descriptions of the motor abnormality produced by systemic administration of the L-type calcium channel agonist Bay K 8644 suggest that the motor phenomenon is likely dystonia. Reports describe twisting movements, impairment locomotion, limb extension, back arching, and tonic-clonic movements (De Sarro et al., 1992; Bolger et al., 1985; Petersen, 1986; O’Neill and Bolger, 1988; Shelton et al., 1987; Bourson et al., 1989; Bianchi et al., 1990; Palmer et al., 1993). FPL 64179, another L-type calcium channel agonist, provokes a similar motor syndrome (Zheng et al., 1991; Rampe et al., 1993). Second, although the motor syndrome was characterized as a form of epilepsy, it does not respond to anticonvulsants such as carbamazepine, diphenylhydantion, phenobarbital, or valproic acid (De Sarro et al., 1992; Shelton et al., 1987; Bianchi et al., 1990; Palmer et al., 1993). Third, the Cacna1a calcium channel mutants clearly implicate calcium dysregulation, including upregulation of L- and N-type calcium channels, in the genesis of dystonia, suggesting that manipulation of calcium homeostasis using drugs in normal mice might have similar effects.

III. DYSTONIA

27.4  SUMMARY AND CONCLUSIONS

27.3.3.2  Motor Disorder (Video Segment 5) Low doses of systemically administered Bay K 8644 cause slowing of movements with occasional momentary abnormal limb positions. Higher doses cause abnormal, severe flexion of the trunk with flexion of the head toward the abdomen, which often causes the mouse to fall. Attempts to move are accompanied by abnormal flexion, extension, or twisting movements of the trunk and limbs; muscle tone is increased. Movements are asymmetric and asynchronous. Generally, activity returns to baseline after ∼120 min. Tonic–clonic seizures are rarely observed after systemic injection of Bay K 8644 and no abnormalities of the EEG are observed (Jinnah et al., 2000). However, on EMG, significant increases are observed in resting muscle activity and prolonged movement-related phasic bursting, consistent with dystonia. A similar motor syndrome is evoked by intracerebral injection of Bay K 8644 or systemic administration of FPL 64176 (Jinnah et al., 2000). L-type calcium channel agonists also induce self-injurious behavior, including self-biting, stiff or Straub tail, and hypersensitivity to auditory stimuli (Jinnah et al., 2000). Thus, the response to Bay K 8644 is not a pure dystonic disorder, but part of a more complex neurobehavioral syndrome. Supplementary data related to this chapter can be found at http://dx.doi.org/10.1016/B978-0-12-4051959.00027-5. 27.3.3.3 Pathophysiology To determine if Bay K 8644 activates specific brain regions, the induction of c-fos was used as a marker of neuronal activation (Jinnah et al., 2003). Despite the extensive distribution of L-type calcium channels throughout brain, c-fos induction after Bay K 8644 challenge is widespread, but not heterogeneous. Particularly robust activation is noted in the striatum, cortex, hippocampus, locus coeruleus, and cerebellum. Involvement of the cerebellum is unlikely because cerebellar microinjection of Bay K 8644 does not induce dystonia (Fan et al., 2012). Additionally, the Bay K 8644-induced dystonic response in mice lacking cerebellar Purkinje cells is comparable to normal mice (Fan et al., 2012), implying that the dystonia induced by peripherally administered Bay K 8644 is not dependent on signaling from the cerebellar cortex. 27.3.3.4 Comment The broad distribution of activation suggests that Bay K 8644 may induce dystonia through its action at several different motor regions, consistent with the idea that dystonia may arise from many different brain regions (Neychev et al., 2011). Indeed, for disorders such as DYT1 dystonia, where the mutant gene product is expressed in many brain regions (Augood et al., 1999), such abnormal signaling from many brain regions may underlie the expression of dystonia.

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27.3.4  Dystonia Caused by Infusion of Ouabain 27.3.4.1 Background Rapid-onset dystonia with parkinsonism (RDP) is characterized by sudden onset of dystonia that is often accompanied by parkinsonian features. The symptoms rapidly evolve over hours to a few weeks and often occur in response to physical or emotional stress. RDP is caused by mutations in the ATP1A3, which encodes the Na+/K+ATPase α3 subunit. Because RDP is associated with lossof-function mutations, brain region-specific infusions of ouabain, a selective blocker of Na+/K+-ATPase α3 activity, were used to create a model of RDP (Calderon et al., 2011). 27.3.4.2  Motor Disorder Videos of the motor dysfunction can be viewed at http://www.nature.com/neuro/journal/v14/n3/full /nn.2753.html#supplementary-information. Infusion of ouabain into the mouse cerebellum produces robust dystonic movements, whereas infusion of ouabain into the striatum causes parkinsonian-like features. Infusions of lower doses of ouabain into both cerebellum and striatum simultaneously evoke mild dyskinesias, but after stress challenge generalized dystonia is observed, reminiscent of the abrupt onset of symptoms after stress in RDP patients. 27.3.4.3 Pathophysiology In this model, the dystonic movements are apparently instigated by the cerebellum because lesions of the deep cerebellar nuclei, the main source of cerebellar output, abolish the dystonia. During dystonic movements, the cerebellar EEG amplitude is significantly increased but cortical EEG is unchanged. However, basal ganglia also play a role as lesions of the centrolateral nucleus of the thalamus, which represents the di-synaptic link between the cerebellum and the basal ganglia, also ameliorate the dystonia. These results suggest that the distorted cerebellar signaling alters basal ganglia function, which, in turn, leads to dystonia. 27.3.4.4 Comment This model demonstrates that communication within a motor network is critical for the expression of dystonic movements. Again, this is consistent with the idea that dystonia may arise from many different brain regions (Neychev et al., 2011).

27.4  SUMMARY AND CONCLUSIONS Animal models are generally used to understand the mechanisms underlying a disorder in humans. Several common themes are emerging from animal models of dystonia that provide clues for understanding the pathophysiology of dystonia in humans.

III. DYSTONIA

27.4 Summary and Conclusions

The following are the supplementary data related to this chapter:

Video Segment 5 Bay K 8644-induced dystonia. These clips demonstrate the sustained twisting postures and slowed movement after systemic administration of 8 mg/kg Bay K 8644.

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27.  MOUSE MODELS OF DYSTONIA

First, the Cacna1a, Scn8a, RDP, and Bay K 8644 mouse models clearly implicate dysfunctional ion homeostasis in dystonia. Indeed, ion channel dysfunction induced by either mutation or pharmacologic intervention induces dystonia. The purpose of animal models is to suggest novel approaches and mechanisms for human disease. As such, the suggestion that ion channel dysfunction may drive dystonia is worthy of investigation and presents a novel approach for unraveling dystonia in humans. In this regard, mutations in PRRT2 and ANO3 have recently been associated with paroxysmal kinesigenic dyskinesia and craniocervical dystonia, respectively (Chen et al., 2011). PRRT2 encodes proline-rich transmembrane protein 2, which may play a role in the localization or stabilization of sodium channels, whereas ANO3 encodes a Ca2+-gated chloride channel highly expressed in striatum (Charlesworth et al., 2012). Next, although studies in humans have traditionally implicated dysfunction of the basal ganglia in dystonia (Marsden and Quinn, 1990; Ondo et al., 1998; Ichinose et al., 1994; Vitek, 2002), more recent functional studies in humans have consistently implicated the cerebellum as well (Ceballos-Baumann and Brooks, 1998; Mazziotta et al., 1998; Odergren et al., 1998; Playford et al., 1998; Kluge et al., 1998; Hutchinson et al., 2000). Mouse models clearly implicate dysfunction of both the basal ganglia and cerebellum in dystonia, whereby the models fall into three subtypes. The FGF14-deficient mice and 3-NP mouse models demonstrate that defects of the basal ganglia can induce dystonia, while Cacna1a mutants and kainate-induced dystonia implicate the cerebellum in dystonia. Still other models, including Bay K 8644, Scn8a, and RDP, suggest that several dysfunctional brain regions may simultaneously contribute to the expression of dystonia. Importantly, the concept that dystonia may arise from the basal ganglia or the cerebellum or a complex combination of motor systems appears to have broad general applicability, as both genetic and drug-induced models fall into each of these subtypes. Given the heterogeneous nature of dystonia in humans and the lessons learned from rodent models, it is reasonable to suppose that the site of dysfunction will not be consistent from patient to patient. The mouse models illustrate the complexity of the disorder and suggest that focusing on a single brain region or gene may be counterproductive to understanding general pathophysiological principles of motor dysfunction in dystonia.

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