Mechanisms of cerebellar gait ataxia

Morton, Susanne M.; Bastian, Amy J.

doi:10.1080/14734220601187741

Cited by 162 publications

(118 citation statements)

References 80 publications

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“…The seemingly restricted vRh concentration in vermal PCs not only exhibits the necessity to create an alternative and optimized method for in vivo expression but also highlights the magnitude of influence that the G i/o pathway has on motor control and the endogenous firing properties of PCs. Numerous examinations of the cerebellum and specifically the medial cerebellar region have indicated that this area plays a pivotal role in regulating extensor tone, sustaining upright stance, and dynamic balance control (18,19,25). It is thought that the cerebellum employs anticipatory and feedback mechanisms to maintain balance during locomotion and that failure in these systems induce an ataxic-like phenotype (19,26,27).…”

Section: Modulation Of Simple Spikes In the Medial Cerebellar Regionsmentioning

confidence: 99%

“…Numerous examinations of the cerebellum and specifically the medial cerebellar region have indicated that this area plays a pivotal role in regulating extensor tone, sustaining upright stance, and dynamic balance control (18,19,25). It is thought that the cerebellum employs anticipatory and feedback mechanisms to maintain balance during locomotion and that failure in these systems induce an ataxic-like phenotype (19,26,27). Behavioral testing revealed that the photostimulation of positive vermal PCs in vRh-GFP PC mice induced changes in motor output.…”

Section: Modulation Of Simple Spikes In the Medial Cerebellar Regionsmentioning

confidence: 99%

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Optogenetic Control of Motor Coordination by Gi/o Protein-coupled Vertebrate Rhodopsin in Cerebellar Purkinje Cells

Gutierrez

Mark

Masseck

et al. 2011

Journal of Biological Chemistry

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The G protein-mediated signaling pathway provides a pivotal module for the adjustment of neuronal networks against physiological or behavioral tasks on a second to minute time scale (1). Among G proteins, the G i/o -mediated signaling pathway is the primary role in which GPCRs 2 mediate their inhibitory action on neuronal excitability (2). The processes and importance of such modulation in cellular and network functions has mainly been investigated with the application of drugs, activating or inhibiting more or less specifically a certain GPCR pathway. Recently, we demonstrated that light-activated vertebrate rhodopsin (vRh) is a suitable alternative to control ion conductances such as G protein-coupled inward rectifying K ϩ channel and voltage-gated Ca 2ϩ channels via pertussis toxin-sensitive G i/o protein-mediated signaling (3). Therefore, vRh may allow for the precise spatiotemporal control of G i/o -mediated pathway in vivo, leading to an investigation that focuses on the function of this pathway in animal behavior or brain functions such as motor coordination.The cerebellum plays a central role in overall motor coordination and motor learning. An extensive array of GPCRs is expressed throughout the brain and is believed to be involved in the modulation of network activity and synaptic plasticity. It has been recognized that the code for motor coordination and balance lies within the firing cadence and output pattern of cerebellar PCs, which are the sole-output neurons from the cerebellar cortex (4, 5). PCs integrate a range of cortical, vestibular, and sensory information via excitatory synaptic input from parallel and climbing fiber pathways and inhibitory synaptic input originating from neighboring interneurons. The PC firing pattern is determined by several factors that include the interplay between excitatory and inhibitory synaptic inputs, several ion channel conductances that support intrinsic firing properties, and modulation by postsynaptic GPCRs like the GABA B receptor (GABA B R) (6 -8). GABA B R activation by application of the selective agonist baclofen leads to a reduction in PC firing most likely due to membrane hyperpolarization induced by G protein-coupled inward rectifying K ϩ channel activation (9 -12). The exact mechanism in which G i/o -mediated GPCR modulation may occur within PCs and how such modulation may influence the single spike pattern and motor coordination has been difficult to address in vivo, as GABA B Rs and other G i/o -coupled receptors are expressed in various cell types in the cerebellum and can only be activated by slowly diffusing drugs.To overcome the kinetic and spatial issues that the pharmacological approach presents and to investigate the functional impact of G i/o protein-mediated modulation on cerebellar function via spike modulation in cerebellar PCs, we created an optogenetic mouse model for the cell type-specific expression of vRh and demonstrated that spike modulation of PCs affects motor coordination. EXPERIMENTAL PROCEDURES Generation and Screening of Tra...

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Section: Modulation Of Simple Spikes In the Medial Cerebellar Regionsmentioning

confidence: 99%

Section: Modulation Of Simple Spikes In the Medial Cerebellar Regionsmentioning

confidence: 99%

Optogenetic Control of Motor Coordination by Gi/o Protein-coupled Vertebrate Rhodopsin in Cerebellar Purkinje Cells

Gutierrez

Mark

Masseck

et al. 2011

Journal of Biological Chemistry

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“…In the cerebellum, the genes Kcna1 and Kcna2 encode the voltagegated potassium channel subunits Kv1.1 and Kv1.2, respectively, which contribute to the low voltage-activated potassium current I Kv1 and are coexpressed in the presynaptic GABAergic pinceaus of spontaneously firing basket cell interneurons that provide a strong inhibitory input to Purkinje cells (5-9). The shunting effect of this inhibitory conductance has been shown through modeling to have a steep correlation with the prolongation of Purkinje cell interspike intervals in vitro (11-13).The cerebellum is involved in the regulation of the initiation and timing of movements and is important for maintaining balance and posture (14). At the core of the cerebellar computational circuitry, the spontaneously spiking Purkinje cells integrate cerebral cortical and sensory, excitatory and inhibitory inputs encoding relevant information in their action potential discharge and communicate the information to the deep cerebellar nuclei for the final output of the cerebellum (15).…”

mentioning

confidence: 99%

“…The cerebellum is involved in the regulation of the initiation and timing of movements and is important for maintaining balance and posture (14). At the core of the cerebellar computational circuitry, the spontaneously spiking Purkinje cells integrate cerebral cortical and sensory, excitatory and inhibitory inputs encoding relevant information in their action potential discharge and communicate the information to the deep cerebellar nuclei for the final output of the cerebellum (15).…”

mentioning

confidence: 99%

A New Kv1.2 Channelopathy Underlying Cerebellar Ataxia

Xie

Harrison

Clapcote

et al. 2010

Journal of Biological Chemistry

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A forward genetic screen of mice treated with the mutagen ENU identified a mutant mouse with chronic motor incoordination. This mutant, named Pingu (Pgu), carries a missense mutation, an I402T substitution in the S6 segment of the voltage-gated potassium channel Kcna2. The gene Kcna2 encodes the voltage-gated potassium channel ␣-subunit Kv1.2, which is abundantly expressed in the large axon terminals of basket cells that make powerful axo-somatic synapses onto Purkinje cells. Patch clamp recordings from cerebellar slices revealed an increased frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents and reduced action potential firing frequency in Purkinje cells, suggesting that an increase in GABA release from basket cells is involved in the motor incoordination in Pgu mice. In line with immunochemical analyses showing a significant reduction in the expression of Kv1 channels in the basket cell terminals of Pgu mice, expression of homomeric and heteromeric channels containing the Kv1.2(I402T) ␣-subunit in cultured CHO cells revealed subtle changes in biophysical properties but a dramatic decrease in the amount of functional Kv1 channels. Pharmacological treatment with acetazolamide or transgenic complementation with wildtype Kcna2 cDNA partially rescued the motor incoordination in Pgu mice. These results suggest that independent of known mutations in Kcna1 encoding Kv1.1, Kcna2 mutations may be important molecular correlates underlying human cerebellar ataxic disease.Voltage-gated potassium channels play a key role in neuronal excitability and plasticity and are critical in establishing resting membrane potential and firing thresholds, repolarizing action potentials, and limiting excitability (1). Channels are unevenly distributed throughout the brain as a whole and also within individual neurons (2-10). Therefore, the particular utility of any given channel depends not only on its specific channel properties and stoichiometry but also on its particular localization and density within a cell or cellular compartment. In the cerebellum, the genes Kcna1 and Kcna2 encode the voltagegated potassium channel subunits Kv1.1 and Kv1.2, respectively, which contribute to the low voltage-activated potassium current I Kv1 and are coexpressed in the presynaptic GABAergic pinceaus of spontaneously firing basket cell interneurons that provide a strong inhibitory input to Purkinje cells (5-9). The shunting effect of this inhibitory conductance has been shown through modeling to have a steep correlation with the prolongation of Purkinje cell interspike intervals in vitro (11-13).The cerebellum is involved in the regulation of the initiation and timing of movements and is important for maintaining balance and posture (14). At the core of the cerebellar computational circuitry, the spontaneously spiking Purkinje cells integrate cerebral cortical and sensory, excitatory and inhibitory inputs encoding relevant information in their action potential discharge and communicate the information to the deep cerebell...

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“…Comumente a perna do lado mais afetado é elevada excessivamente durante a fase de balanço por flexão excessiva do quadril e joelho, e depois desce abruptamente e com força incontrolável. A trajetória de andar, muitas vezes, se desvia de forma irregular e pacientes têm dificuldade em parar, especialmente se for realizada rapidamente 12 .…”

Section: Introductionunclassified

Atendimento Fisioterapêutico para Indivíduos com Ataxia Espinocerebelar: Uma Revisão da Literatura

Artigas

Ayres

Noll

et al. 2013

RNC

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RESUMOA ataxia espinocerebelar (AEC) é uma patologia caracterizada pelo déficit na execução de movimentos coordenados com progressiva oscilação postural associada à dificuldade de manutenção do equilíbrio e diversas outras alterações motoras. A marcha pode ficar atáxica, com ampliação da base de sustentação, instabilidade, passos irregulares e mais lentos, lateropulsão e tremor na amplitude de movimento, sendo o tratamento fisioterapêutico uma importante alternativa para a melhora das disfunções decorrentes desta patologia. Objetivo. Realizar, com base na literatura científica, uma revisão sobre as estratégias fisioterapêuticas no tratamento da ataxia espinocerebelar. Método. Pesquisaram-se as bases de dados Medline e SciELO de 2001 a 2011, considerando os unitermos: ataxia espinocerebelar, Fisioterapia, tratamento, reabilitação e seus correlatos em inglês. Resultados. Foram encontrados 33 estudos que tivessem como tema principal a ataxia, sendo excluídos 20 artigos, pois estes não relatavam a abordagem fisioterapêutica para este tipo de patologia. Após análise, 13 referências foram utilizadas. Conclusões. Após a realização deste estudo, destaca--se a importância da Fisioterapia no tratamento dos portadores de AEC, em função dos benefícios promovidos, visto que nos estudos encontrados os indivíduos apresentaram melhora dos sintomas decorrentes desta patologia. Limitações metodológicas observadas sugerem a necessidade de maior rigor em futuras pesquisas.Unitermos. Ataxia, Fisioterapia, Reabilitação, Exercício.Citação. Artigas NR, Ayres JS, Noll J, Peralles SRN, Borges MK, Brito CIB. Atendimento Fisioterapêutico para Indivíduos com Ataxia Espinocerebelar: Uma Revisão da Literatura. ABSTRACTThe spinocerebellar ataxia (SCA) is a disorder characterized by deficits in the execution of coordinated movements with progressive postural sway associated with difficulty in maintaining balance and various other motor disorders. The gait may be ataxic, with broadening the base of support, instability, irregular steps and slow, lateropulsion and trembling in range of motion, so that physical therapy is an important alternative for the improvement of the disorders of this pathology. Objective. Make, based on scientific literature, a review of physical therapy strategies in the treatment of spinocerebellar ataxia. Method. The study researches the databases Medline and SciELO from 2001 to 2011, considering the following keywords: ataxia espinocerebelar, Fisioterapia, tratamento, reabilitação and its correlates in English. Results. We found 33 studies that had as its main theme ataxia, 20 articles were excluded because they did not report the physical therapy approach for this type of pathology. After review, 13 references were used. Conclusions. After this study, the importance of physical therapy in the treatment of patients with SCA becomes obvious, according to the benefits promoted, as all studies found an improvement of symptoms of this pathology. Methodological limitations observed suggest the need for greater rigor in futur...

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Mechanisms of cerebellar gait ataxia

Cited by 162 publications

References 80 publications

Optogenetic Control of Motor Coordination by Gi/o Protein-coupled Vertebrate Rhodopsin in Cerebellar Purkinje Cells

Optogenetic Control of Motor Coordination by Gi/o Protein-coupled Vertebrate Rhodopsin in Cerebellar Purkinje Cells

A New Kv1.2 Channelopathy Underlying Cerebellar Ataxia

Atendimento Fisioterapêutico para Indivíduos com Ataxia Espinocerebelar: Uma Revisão da Literatura

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