Regional cerebral glucose utilization reveals widespread abnormalities in the motor system of the rat mutant dystonic

Brown, Lucy L.; Lorden, Joan F.

doi:10.1523/jneurosci.09-11-04033.1989

Cited by 43 publications

(26 citation statements)

References 27 publications

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“…These abnormalities resembled those previously identified in nonpenetrant human mutation carriers who, like the Tor1a ΔE/+ mice, do not exhibit abnormal involuntary movements (6). Tor1a ΔE/+ mice also exhibit increased metabolic activity in the dorsal cerebellar vermis, a finding consistently identified in manifesting and nonmanifesting human DYT1 carriers (7,9) and in experimental rodent models of dystonia (20)(21)(22). The similarity of these findings indicate that DYT1 mutant torsinA can produce similar CNS changes in mice and humans, and suggest that Tor1a ΔE/+ mice are a model of human nonmanifesting DYT1 mutation carriers.…”

Section: Discussionsupporting

confidence: 82%

“…Metabolic activity was found to be focally increased in the dorsal cerebellar vermis, which connects via the thalamus to cortical motor areas. Interestingly, cerebellar hypermetabolism has been described consistently in manifesting and nonmanifesting human DYT1 carriers (7, 9) and in a genetic rat model of dystonia (20). The observed increase in cerebellar metabolic activity may also reflect a compensatory phenomenon (29).…”

Section: Discussionmentioning

confidence: 96%

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Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ

Árgyelán

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

112

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The factors that determine symptom penetrance in inherited disease are poorly understood. Increasingly, magnetic resonance diffusion tensor imaging (DTI) and PET are used to separate alterations in brain structure and function that are linked to disease symptomatology from those linked to gene carrier status. One example is DYT1 dystonia, a dominantly inherited movement disorder characterized by sustained muscle contractions, postures, and/or involuntary movements. This form of dystonia is caused by a 3-bp deletion (i.e., ΔE) in the TOR1A gene that encodes torsinA. Carriers of the DYT1 dystonia mutation, even if clinically nonpenetrant, exhibit abnormalities in cerebellothalamocortical (CbTC) motor pathways. However, observations in human gene carriers may be confounded by variability in genetic background and age. To address this problem, we implemented a unique multimodal imaging strategy in a congenic line of DYT1 mutant mice that contain the ΔE mutation in the endogenous mouse torsinA allele (i.e., DYT1 knock-in). Heterozygous knock-in mice and littermate controls underwent micro-PET followed by ex vivo high-field DTI and tractographic analysis. Mutant mice, which do not display abnormal movements, exhibited significant CbTC tract changes as well as abnormalities in brainstem regions linking cerebellar and basal ganglia motor circuits highly similar to those identified in human nonmanifesting gene carriers. Moreover, metabolic activity in the sensorimotor cortex of these animals was closely correlated with individual measures of CbTC pathway integrity. These findings further link a selective brain circuit abnormality to gene carrier status and demonstrate that DYT1 mutant torsinA has similar effects in mice and humans.connectivity | regional metabolism | brain networks I n recent years, advanced imaging technologies such as PET and magnetic resonance diffusion tensor imaging (DTI) have provided unique information regarding the impact of specific genetic mutations on brain structure and function. However, to control for variability in genetic background and additional confounders such as age and sex, many more mutation carriers (and control subjects) are required than can conveniently be scanned, even in a multicenter design. Human imaging studies may also suffer from relatively low spatial resolution and sensitivity. These considerations motivated the current study in which high field magnetic resonance DTI was performed ex vivo in an experimental genetic model of a brain disorder.Primary dystonia is a childhood-onset neurological illness characterized by disabling abnormal involuntary movements without consistent brain lesions on routine structural brain imaging or at postmortem analysis (1). This disorder is associated with several genotypes (2). DYT1 dystonia, the most common inherited form of the disease, is caused by a dominantly inherited 3-bp in-frame deletion in the TOR1A gene that removes a single glutamic acid (ΔE) from the torsinA protein (3). This lowprevalence mutation (approximately 1 in 30,000...

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 96%

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Uluğ

Árgyelán

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

112

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“…Dysfunctional cerebellar output is a major contributor to the generalized dystonia of the dystonic rat and lesions of the cerebellum mitigate the dystonia (LeDoux et al 1993(LeDoux et al , 1995. Cerebellar abnormalities in this rat model include decreased GABAergic activity in the cerebellar nuclei and defective climbing fiber innervation of PCs (Beales et al 1990;Brown and Lorden 1989;Lorden et al 1985;Stratton et al 1988). The oscillations in the cerebellar cortex of the tg mouse provide another example of abnormal cerebellar activity in a dystonic syndrome.…”

Section: Discussionmentioning

confidence: 99%

Low-Frequency Oscillations in the Cerebellar Cortex of the Tottering Mouse

Chen¹,

Popa²,

Wang

et al. 2009

Journal of Neurophysiology

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EJ, Ebner TJ. Low-frequency oscillations in the cerebellar cortex of the tottering mouse. J Neurophysiol 101: 234 -245, 2009. First published November 5, 2008 doi:10.1152/jn.90829.2008. The tottering mouse is an autosomal recessive disorder involving a missense mutation in the gene encoding P/Q-type voltage-gated Ca 2ϩ channels. The tottering mouse has a characteristic phenotype consisting of transient attacks of dystonia triggered by stress, caffeine, or ethanol. The neural events underlying these episodes of dystonia are unknown. Flavoprotein autofluorescence optical imaging revealed transient, low-frequency oscillations in the cerebellar cortex of anesthetized and awake tottering mice but not in wild-type mice. Analysis of the frequencies, spatial extent, and power were used to characterize the oscillations. In anesthetized mice, the dominant frequencies of the oscillations are between 0.039 and 0.078 Hz. The spontaneous oscillations in the tottering mouse organize into high power domains that propagate to neighboring cerebellar cortical regions. In the tottering mouse, the spontaneous firing of 83% (73/88) of cerebellar cortical neurons exhibit oscillations at the same low frequencies. The oscillations are reduced by removing extracellular Ca 2ϩ and blocking L-type Ca 2ϩ channels. The oscillations are likely generated intrinsically in the cerebellar cortex because they are not affected by blocking AMPA receptors or by electrical stimulation of the parallel fiber-Purkinje cell circuit. Furthermore, local application of an L-type Ca 2ϩ agonist in the tottering mouse generates oscillations with similar properties. The beam-like response evoked by parallel fiber stimulation is reduced in the tottering mouse. In the awake tottering mouse, transcranial flavoprotein imaging revealed low-frequency oscillations that are accentuated during caffeine-induced attacks of dystonia. During dystonia, oscillations are also present in the face and hindlimb electromyographic (EMG) activity that become significantly coherent with the oscillations in the cerebellar cortex. These low-frequency oscillations and associated cerebellar cortical dysfunction demonstrate a novel abnormality in the tottering mouse. These oscillations are hypothesized to be involved in the episodic movement disorder in this mouse model of episodic ataxia type 2.

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“…In particular, the correlations that we obtained in control mice are similar to values previously reported in hamsters and rats (Brown and Lorden, 1989;Richter et al, 1998). For specific examples, mice, rats, and hamsters show positive correlations between the cerebellar nuclei (medial and interpositus) and the red nucleus.…”

Section: Discussionsupporting

confidence: 89%

TorsinA and the Pathophysiology of DYT1 Dystonia

Zhao¹

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Regional cerebral glucose utilization reveals widespread abnormalities in the motor system of the rat mutant dystonic

Cited by 43 publications

References 27 publications

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice

Low-Frequency Oscillations in the Cerebellar Cortex of the Tottering Mouse

TorsinA and the Pathophysiology of DYT1 Dystonia

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