Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes mice
Recent evidence suggests that dystonia, a movement disorder characterized by sustained involuntary muscle contractions, can be associated with cerebellar abnormalities. The basis for how functional changes in the cerebellum can cause dystonia is poorly understood. Here we identify alterations in phy...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-07-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114000813 |
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| author | Katiuska Luna-Cancalon Kristine M. Sikora Samuel S. Pappas Vikrant Singh Heike Wulff Henry L. Paulson Margit Burmeister Vikram G. Shakkottai |
| author_facet | Katiuska Luna-Cancalon Kristine M. Sikora Samuel S. Pappas Vikrant Singh Heike Wulff Henry L. Paulson Margit Burmeister Vikram G. Shakkottai |
| author_sort | Katiuska Luna-Cancalon |
| collection | DOAJ |
| description | Recent evidence suggests that dystonia, a movement disorder characterized by sustained involuntary muscle contractions, can be associated with cerebellar abnormalities. The basis for how functional changes in the cerebellum can cause dystonia is poorly understood. Here we identify alterations in physiology in Atcayji-hes mice which in addition to ataxia, have an abnormal gait with hind limb extension and toe walking, reminiscent of human dystonic gait. No morphological abnormalities in the brain accompany the dystonia, but partial cerebellectomy causes resolution of the stiff-legged gait, suggesting that cerebellar dysfunction contributes to the dystonic gait of Atcayji-hes mice. Recordings from Purkinje and deep cerebellar nuclear (DCN) neurons in acute brain slices were used to determine the physiological correlates of dystonia in the Atcayji-hes mice. Approximately 50% of cerebellar Purkinje neurons fail to display the normal repetitive firing characteristic of these cells. In addition, DCN neurons exhibit increased intrinsic firing frequencies with a subset of neurons displaying bursts of action potentials. This increased intrinsic excitability of DCN neurons is accompanied by a reduction in after-hyperpolarization currents mediated by small-conductance calcium-activated potassium (SK) channels. An activator of SK channels reduces DCN neuron firing frequency in acute cerebellar slices and improves the dystonic gait of Atcayji-hes mice. These results suggest that a combination of reduced Purkinje neuron activity and increased DCN intrinsic excitability can result in a combination of ataxia and a dystonia-like gait in mice. |
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| id | doaj.art-1699c638432d4e73ae409866e44eb80f |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T07:56:16Z |
| publishDate | 2014-07-01 |
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| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-1699c638432d4e73ae409866e44eb80f2022-12-21T21:57:40ZengElsevierNeurobiology of Disease1095-953X2014-07-0167140148Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes miceKatiuska Luna-Cancalon0Kristine M. Sikora1Samuel S. Pappas2Vikrant Singh3Heike Wulff4Henry L. Paulson5Margit Burmeister6Vikram G. Shakkottai7Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USAProgram in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Neurology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of California, Davis, CA 95616, USADepartment of Pharmacology, University of California, Davis, CA 95616, USADepartment of Neurology, University of Michigan, Ann Arbor, MI 48109, USAMolecular & Behavioral Neuroscience Institute, Departments of Psychiatry, Computational Medicine & Bioinformatics and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USADepartment of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author at: 4009 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.Recent evidence suggests that dystonia, a movement disorder characterized by sustained involuntary muscle contractions, can be associated with cerebellar abnormalities. The basis for how functional changes in the cerebellum can cause dystonia is poorly understood. Here we identify alterations in physiology in Atcayji-hes mice which in addition to ataxia, have an abnormal gait with hind limb extension and toe walking, reminiscent of human dystonic gait. No morphological abnormalities in the brain accompany the dystonia, but partial cerebellectomy causes resolution of the stiff-legged gait, suggesting that cerebellar dysfunction contributes to the dystonic gait of Atcayji-hes mice. Recordings from Purkinje and deep cerebellar nuclear (DCN) neurons in acute brain slices were used to determine the physiological correlates of dystonia in the Atcayji-hes mice. Approximately 50% of cerebellar Purkinje neurons fail to display the normal repetitive firing characteristic of these cells. In addition, DCN neurons exhibit increased intrinsic firing frequencies with a subset of neurons displaying bursts of action potentials. This increased intrinsic excitability of DCN neurons is accompanied by a reduction in after-hyperpolarization currents mediated by small-conductance calcium-activated potassium (SK) channels. An activator of SK channels reduces DCN neuron firing frequency in acute cerebellar slices and improves the dystonic gait of Atcayji-hes mice. These results suggest that a combination of reduced Purkinje neuron activity and increased DCN intrinsic excitability can result in a combination of ataxia and a dystonia-like gait in mice.http://www.sciencedirect.com/science/article/pii/S0969996114000813DystoniaAtaxiaCerebellumPurkinje cellsDeep cerebellar nucleiPatch-clamp |
| spellingShingle | Katiuska Luna-Cancalon Kristine M. Sikora Samuel S. Pappas Vikrant Singh Heike Wulff Henry L. Paulson Margit Burmeister Vikram G. Shakkottai Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes mice Neurobiology of Disease Dystonia Ataxia Cerebellum Purkinje cells Deep cerebellar nuclei Patch-clamp |
| title | Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes mice |
| title_full | Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes mice |
| title_fullStr | Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes mice |
| title_full_unstemmed | Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes mice |
| title_short | Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcayji-hes mice |
| title_sort | alterations in cerebellar physiology are associated with a stiff legged gait in atcayji hes mice |
| topic | Dystonia Ataxia Cerebellum Purkinje cells Deep cerebellar nuclei Patch-clamp |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114000813 |
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