Cerebellectomy Eliminates the Motor Syndrome of the Genetically Dystonic Rat

LeDoux, Mark S.; Lorden, Joan F.; Ervin, Jeff M.

doi:10.1006/exnr.1993.1064

Cited by 113 publications

(84 citation statements)

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“…If the cerebellum receives abnormal trigeminal inputs from maladaptive learning processes, then the cerebellum will support and maintain this abnormal motor learning that originated in trigeminal blink circuits. Like previous studies indicating that the cerebellum is essential for the expression of dystonic movements, [118-120] the Schicatano et al (1997) rat model [100] predicts that the cerebellum is essential for maintaining spasms of eyelid closure created by abnormal trigeminal blink circuit motor learning enabled by a dysfunctional basal ganglia input This focus on abnormal motor learning as the proximate cause of BEB points to novel approaches to alleviate spasms of eyelid closure in BEB through modifying trigeminal motor learning.…”

Section: Introductionsupporting

confidence: 76%

Animal Models for Investigating Benign Essential Blepharospasm

Evinger

2013

Current Neuropharmacology

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The focal dystonia benign essential blepharospasm (BEB) affects as many as 40,000 individuals in the United States. This dystonia is characterized by trigeminal hyperexcitability, photophobia, and most disabling of the symptoms, involuntary spasms of lid closure that can produce functional blindness. Like many focal dystonias, BEB appears to develop from the interaction between a predisposing condition and an environmental trigger. The primary treatment for blepharospasm is to weaken the eyelid-closing orbicularis oculi muscle to reduce lid spasms. There are several animal models of blepharospasm that recreate the spasms of lid closure in order to investigate pharmacological treatments to prevent spasms of lid closure. One animal model attempts to mimic the predisposing condition and environmental trigger that give rise to BEB. This model indicates that abnormal interactions among trigeminal blink circuits, basal ganglia, and the cerebellum are the neural basis for BEB.

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Section: Introductionsupporting

confidence: 76%

Animal Models for Investigating Benign Essential Blepharospasm

Evinger

2013

Current Neuropharmacology

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“…In rats, deficiency of caytaxin results in generalized dystonia (dt) (Xiao and Ledoux, 2005). Cerebellectomy rescues the severe motor symptoms and prolongs the lifespan of dt rats (LeDoux et al, 1993). Electrophysiological and biochemical studies of dt rats define the olivocerebellar pathway, particularly the climbing fiber projection to Purkinje cells, as main sites of dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Cayman ataxia protein caytaxin is transported by kinesin along neurites through binding to kinesin light chains

Aoyama

Hata

Nakao

et al. 2009

Journal of Cell Science

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“…However, unlike human Cayman ataxia, the mutations in the dystonic rat model and those in the jittery and sidewinder mouse mutants are generally lethal as they probably cause more drastic changes in BNIP-H structure and quantity than the mutations observed in humans (Xiao and LeDoux, 2005). Interestingly, cerebellectomy could partially rescue the phenotype and prolong the lifespan of the dystonic rat (LeDoux et al, 1993), supporting the notion that BNIP-H does play an important role in the correct functioning of the cerebellum for movement control. Indeed, induction of dystonia upon injection of low doses of kainic acid into cerebellar vermis of mice depends on glutamatergic activation (Pizoli et al, 2002).…”

Section: Discussionmentioning

confidence: 81%

Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels

Buschdorf

Chew

Zhang

et al. 2006

Journal of Cell Science

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Human Cayman ataxia and mouse or rat dystonia are linked to mutations in the genes ATCAY (Atcay) that encode BNIP-H or Caytaxin, a brain-specific member of the BNIP-2 family. To explore its possible role(s) in neuronal function, we used protein precipitation and matrix-assisted laser desorption/ionisation mass spectrometry and identified kidney-type glutaminase (KGA) as a novel partner of BNIP-H. KGA converts glutamine to glutamate, which could serve as an important source of neurotransmitter. Co-immunoprecipitation with specific BNIP-H antibody confirmed that endogenous BNIP-H and KGA form a physiological complex in the brain, whereas binding studies showed that they interact with each other directly. Immunohistochemistry and in situ hybridisation revealed high BNIP-H expression in hippocampus and cerebellum, broadly overlapping with the expression pattern previously reported for KGA. Significantly, BNIP-H expression was activated in differentiating neurons of the embryonic carcinoma cell line P19 whereas its overexpression in rat pheochromocytoma PC12 cells relocalised KGA from the mitochondria to neurite terminals. It also reduced the steady-state levels of glutamate by inhibiting KGA enzyme activity. These results strongly suggest that through binding to KGA, BNIP-H could regulate glutamate synthesis at synapses during neurotransmission. Thus, loss of BNIP-H function could render glutamate excitotoxicity or/and deregulated glutamatergic activation, leading to ataxia, dystonia or other neurological disorders.

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Cerebellectomy Eliminates the Motor Syndrome of the Genetically Dystonic Rat

Cited by 113 publications

References 0 publications

Animal Models for Investigating Benign Essential Blepharospasm

Animal Models for Investigating Benign Essential Blepharospasm

Cayman ataxia protein caytaxin is transported by kinesin along neurites through binding to kinesin light chains

Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels

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