The Experts below are selected from a list of 240 Experts worldwide ranked by ideXlab platform
Ellen J. Hess - One of the best experts on this subject based on the ideXlab platform.
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Mouse Models of Episodic Ataxia Type 2
Movement Disorders, 2015Co-Authors: Samuel J. Rose, Ellen J. HessAbstract:Episodic ataxia type 2 (EA2) is a disorder characterized by acute attacks of ataxia precipitated by stress, ethanol, and caffeine. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1 pore-forming subunit of the Cav2.1 (P/Q-type) voltage-gated calcium channel. Several Mouse strains, including Tottering mice, carry loss-of-function mutations in the Cacna1a gene and have been used to investigate the pathomechanisms of EA2. Like EA2 patients, Tottering mice exhibit attacks of motor dysfunction triggered by stress, ethanol, and caffeine. The cerebellum and specifically cerebellar Purkinje cells are implicated in Tottering Mouse attacks. Like EA2 patients, drugs that restore Purkinje cell pacemaking, such as 4-aminopyradine, block Tottering attacks. Other Mouse strains, such as rocker, leaner, and engineered strains, display a range of phenotypes, from mild, paroxysmal motor dysfunction to chronic dystonia, similar to the range of neurological problems exhibited by EA2 patients. Cacna1a mutant mice have provided insights into the neurobiology of EA2 and into the mechanisms underlying treatments and may, therefore, prove useful for developing novel and more efficacious therapeutics.
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Stress, caffeine and ethanol trigger transient neurological dysfunction through shared mechanisms in a Mouse calcium channelopathy
Neurobiology of disease, 2012Co-Authors: Robert S. Raike, Hyder A. Jinnah, Catherine J.c. Weisz, Freek E. Hoebeek, Matthew C. Terzi, Chris I. De Zeeuw, Arn M. J. M. Van Den Maagdenberg, Ellen J. HessAbstract:Several episodic neurological disorders are caused by ion channel gene mutations. In patients, transient neurological dysfunction is often evoked by stress, caffeine and ethanol, but the mechanisms underlying these triggers are unclear because each has diverse and diffuse effects on the CNS. Attacks of motor dysfunction in the CaV2.1 calcium channel Mouse mutant Tottering are also triggered by stress, caffeine and ethanol. Therefore, we used the Tottering Mouse attacks to explore the pathomechanisms of the triggers. Despite the diffuse physiological effects of these triggers, ryanodine receptor blockers prevented attacks induced by all of them. In contrast, compounds that potentiate ryanodine receptors triggered attacks suggesting a convergent biochemical pathway. Tottering Mouse attacks were both induced and blocked within the cerebellum suggesting that the triggers act locally to instigate attacks. In fact, stress, caffeine and alcohol precipitated attacks in CaV2.1 mutant mice in which genetic pathology was limited to cerebellar Purkinje cells, suggesting that the triggers initiate dysfunction within a specific brain region. The surprising biochemical and anatomical specificity of the triggers and the discovery that the triggers operate through shared mechanisms suggest that it is possible to develop targeted therapies aimed at blocking the induction of episodic neurological dysfunction, rather than treating the symptoms once provoked.
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Motor dysfunction in the Tottering Mouse is linked to cerebellar spontaneous low frequency oscillations revealed by flavoprotein autofluorescence optical imaging
Photons and Neurons, 2009Co-Authors: Gang Chen, Laurentiu S. Popa, Xinming Wang, Wangcai Gao, Justin Barnes, Claudia M. Hendrix, Ellen J. Hess, Timothy J. EbnerAbstract:Flavoprotein autofluorescence optical imaging is developing into a powerful research tool to study neural activity, particularly in vivo. In this study we used this imaging technique to investigate the neuronal mechanism underlying the episodic movement disorder that is characteristic of the Tottering (tg) Mouse, a model of episodic ataxia type 2. Both EA2 and the tg Mouse are caused by mutations in the gene encoding Ca v 2.1 (P/Q-type) voltage-gated Ca 2+ channels. These mutations result in a reduction in P/Q Ca 2+ channel function. Both EA2 patients and tg mice have a characteristic phenotype consisting of transient motor attacks triggered by stress, caffeine or ethanol. The neural events underlying these episodes of dystonia are unknown. Flavoprotein autofluorescence optical imaging revealed spontaneous, transient, low frequency oscillations in the cerebellar cortex of the tg Mouse. Lasting from 30 - 120 minutes, the oscillations originate in one area then spread to surrounding regions over 30 - 60 minutes. The oscillations are reduced by removing extracellular Ca 2+ and blocking Ca v 1.2/1.3 (L-type) Ca 2+ channels. The oscillations are not affected by blocking AMPA receptors or by electrical stimulation of the parallel fiber - Purkinje cell circuit, suggesting the oscillations are generated intrinsically in the cerebellar cortex. Conversely, L-type Ca 2+ agonists generate oscillations with similar properties. In the awake tg Mouse, transcranial flavoprotein imaging revealed low frequency oscillations that are accentuated during caffeine induced attacks of dystonia. The oscillations increase during the attacks of dystonia and are coupled to oscillations in face and hindlimb EMG activity. These transient oscillations and the associated cerebellar dysfunction provide a novel mechanism by which an ion channel disorder results in episodic motor dysfunction.
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Low-frequency oscillations in the cerebellar cortex of the Tottering Mouse.
Journal of neurophysiology, 2008Co-Authors: Gang Chen, Laurentiu S. Popa, Xinming Wang, Wangcai Gao, Justin Barnes, Claudia M. Hendrix, Ellen J. Hess, Timothy J. EbnerAbstract:The Tottering Mouse is an autosomal recessive disorder involving a missense mutation in the gene encoding P/Q-type voltage-gated Ca2+ channels. The Tottering Mouse has a characteristic phenotype co...
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Potassium Channel Blockers Inhibit the Triggers of Attacks in the Calcium Channel Mouse Mutant Tottering
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005Co-Authors: Catherine J.c. Weisz, Robert S. Raike, Luis E Soria-jasso, Ellen J. HessAbstract:Humans with the disorder episodic ataxia type 2 (EA2) and the Tottering Mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and Mouse disorders result from mutations in CACNA1A, the gene encoding the alpha(1)2.1 subunit of Ca(v)2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K(v) voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K(v) channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in Tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K(v) channels, reduced the frequency of restraint- and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in Tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K(v) channels, required comparatively higher doses. These results suggest that aminopyridines block Tottering Mouse attacks via cerebellar K(v) channels. That both stress- and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in Tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.
Louise C. Abbott - One of the best experts on this subject based on the ideXlab platform.
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Neural cell proliferation and survival in the hippocampus of adult CaV 2.1 calcium ion channel mutant mice
Brain research, 2016Co-Authors: Fikru Nigussie, Pei-san Huang, Kris Lukauskis, Bhupinder Bawa, Eid A. Moussa, Louise C. AbbottAbstract:Abstract Tottering mutant mice carry a mutation in the pore-forming subunit (α1A) of Ca V 2.1 (P/Q-type) voltage-gated calcium ion (Ca 2+ ) channels resulting in reduced neuronal Ca 2+ current density. We assessed male Tottering mice for spatial learning using the Morris water maze. Tottering mice performed worse than wild type mice, suggesting abnormal hippocampal function. Because Ca 2+ influx via voltage-dependent Ca 2+ channels regulates neuronal survival and function, we assessed hippocampus volume and cell density using hematoxylin and eosin stained serial sections. Adult hippocampal neurogenesis was assessed using 5-bromo-2′-deoxyuridine (BrdU) labeling with fluorescent immunohistochemistry (IHC) and proliferating cell nuclear antigen (PCNA) with diaminobenzidine IHC. We double-labeled neurons using fluorescence IHC with BrdU-neuronal nuclei (Neu-N) or double labeling of astrocytes using BrdU-glial fibrillary protein, respectively, to assess cell proliferation and survival. We assessed numbers of dying cells using fluoro-Jade histochemistry. Decreased hippocampal volume, increased dentate hilar and hippocampal CA1 cell densities were observed in Tottering mice compared to wild type mice. Cell proliferation was increased in the hilus and CA2 region of Tottering mice compared to wild type mice. Dendritic intersections in Sholl analysis were decreased for Tottering Mouse CA1 pyramidal neurons compared to wild type mice. The increased regional cell density coincides with increases in cell proliferation in similar, non-neurogenic areas of the hippocampus of Tottering mice. Thus, hippocampal alterations observed in adult Tottering mice appear to result from changes in neuronal morphology and proliferation in non-neurogenic areas of the hippocampus, and less through altered adult hippocampal neurogenesis or cell death.
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Striatal expression of Homer1a is affected by genotype but not dystonic phenotype of Tottering mice: a model of spontaneously occurring motor disturbances.
Neuroscience letters, 2011Co-Authors: Felice Iasevoli, Louise C. Abbott, Maria Cicale, Andrea De BartolomeisAbstract:Abstract Tottering ( tg ) mice carry a missense mutation in the gene coding for P/Q-type voltage-dependent Ca 2+ channels (VDCCs). Aberrant functioning of P/Q-type VDCCs results in molecular alterations in Ca 2+ currents and in glutamate and dopamine systems. As a consequence, Tottering mice exhibit mild ataxia, spontaneous epilepsy, and paroxysmal dyskinesia. In this study, we evaluated whether the Tottering mice genotype (homozygous vs . heterozygous) and abnormal movement phenotype (mice exhibiting paroxysmal dyskinesia vs . mice not exhibiting dyskinesia) may affect the expression of Homer1a . Homer1a is a gene whose expression is modulated by glutamate, dopamine and Ca 2+ concentrations. Over-expression of Homer1a has been described in epilepsy and motor dysfunctions. Thereby, changes in Homer1a expression could take place in Tottering mice. Studying the expression profile of this gene may shed light on the molecular events occurring in Tottering mice. Moreover, Tottering mice may represent a valuable animal model for investigating Homer1a involvement in motor disorders. Homer1a expression was decreased in all striatal subregions, with the exclusion of the dorsolateral caudate-putamen, in heterozygous mice compared to wild-type and homozygous mice. Gene expression was decreased in the core of the accumbens in mice exhibiting paroxysmal dyskinesia compared to wild-type mice and to mice not exhibiting dyskinesia. These results demonstrate that the Tottering Mouse genotype may affect striatal expression of Homer1a , possibly as a result of imbalance between Ca 2+ channels subtypes or Ca 2+ -related molecules in heterozygous vs . homozygous mice.
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Alterations in Intracellular Calcium Ion Concentrations in Cerebellar Granule Cells of the CACNA1A Mutant Mouse, Leaner, During Postnatal Development
Neurotoxicity Research, 2011Co-Authors: Bhupinder Bawa, Louise C. AbbottAbstract:Maintaining calcium ion (Ca^2+) homeostasis is crucial for normal neuronal function. Altered Ca^2+ homeostasis interferes with Ca^2+ signaling processes and affects neuronal survival. In this study, we used homozygous leaner and Tottering mutant mice, which carry autosomal recessive mutations in the gene coding for the α_1A pore forming subunit of Ca_V2.1 (P/Q-type) voltage-gated calcium channels (VGCC). Leaner mice show severe ataxia and epilepsy, while Tottering mice are less severely affected. Leaner cerebellar granule cells (CGC) show extensive apoptotic cell death that peaks at postnatal (P) day 20 and continues into adulthood. Intracellular Ca^2+ ([Ca^2+]_i) concentrations in leaner and Tottering Mouse Purkinje cells have been described, but [Ca^2+]_i concentrations have not been reported for granule cells, the largest neuronal population of the cerebellum. Using the ratiometric dye, Fura-2 AM, we investigated the role of Ca^2+ homeostasis in CGC death during postnatal development by demonstrating basal [Ca^2+]_i, depolarization induced Ca^2+ transients, and Ca^2+ transients after completely blocking Ca_V2.1 VGCC. From P20 onward, basal [Ca^2+]_i levels in leaner CGC were significantly lower compared to age-matched wild-type CGC. We also compared basal [Ca^2+]_i levels in leaner and wild-type CGC to basal [Ca^2+]_i in Tottering CGC. Potassium chloride induced depolarization revealed no significant difference in Ca^2+ transients between leaner and wild-type CGC, indicating that even though leaner CGC have dysfunctional P/Q-type VGCC, Ca^2+ transients after depolarization are the same. This suggests that other VGCC are compensating for the dysfunctional P/Q channels. This finding was further confirmed by completely blocking Ca_V2.1 VGCC using ω-Agatoxin IV-A.
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Cerebellar volume decreases in the Tottering Mouse are specific to the molecular layer.
Brain research bulletin, 1995Co-Authors: Krystyna R. Isaacs, Louise C. AbbottAbstract:Abstract The volume of the cerebellum as a whole and the volume of the molecular layer per Purkinje cell in adult Tottering ( tg tg ) and Tottering/leaner ( tg tg la ) mice were reduced when compared with normal age-matched wild type mice (+/+). No changes in the volume of the granule cell layer or white matter layer were detected, suggesting that the mutation effects were limited to the molecular layer of the cerebellum. The density of Purkinje cells and the total number of Purkinje cells did not vary between groups. The cerebellar and body weights were decreased in tg tg and tg tg la mice compared with +/+ mice.
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Increased methionine-enkephalin levels in genetically epileptic (tg/tg) mice.
Brain research bulletin, 1991Co-Authors: Vimal Patel, Louise C. Abbott, Anil K. Rattan, Gopi A. TejwaniAbstract:Abstract Recent experimental data indicate that endogenous brain ligands for the opioid receptors such as enkephalins, beta-endorphin (β-End) and dynorphin (Dyn) may be involved in both generalized and partial seizures. The “Tottering” (tg/tg) Mouse provides an electrophysiological representation of generalized spontaneous human epilepsy. These mice exhibit behavioral absence seizures with accompanying spike-wave discharges. Methionine-enkephalin (M-Enk), β-End and Dyn levels in various regions of brain were measured by radioimmunoassay (RIA) in 15–18-week-old tg/tg and control (+ / +) mice to elucidate the relation between seizures and the opioid system. β-End and Dyn levels were similar in tg/tg and +/+ mice. However, M-Enk levels were significantly increased in the striatum, cortex, pons and medulla of the tg/tg mice. Our data suggest that in the Tottering Mouse model of generalized epilepsy there is an alteration of enkephalinergic pathways and not of the endorphinergic or dynorphinergic pathways.
Etienne Pralong - One of the best experts on this subject based on the ideXlab platform.
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Noradrenaline reduces synaptic responses in normal and Tottering Mouse entorhinal cortex via α2 receptors
Neuroscience Letters, 1994Co-Authors: Etienne Pralong, Pierre J. MagistrettiAbstract:The effects of noradrenaline (NA) on synaptic responses in layer II of the entorhinal cortex (EC) were studied in normal and spontaneously epileptic mutant mice Tottering using intracellular recording in a slice preparation. Neither the membrane properties of neurones nor the responses to NA differed between normal and Tottering mice. NA (50 microM) hyperpolarized most (29/54) of the neurones via alpha 2 adrenergic receptors. Synaptic responses of EC neurones were complex. NA (10-100 microM) reduced all the components of the synaptic response in a concentration-dependent and reversible manner. The pharmacological properties of the inhibitory effect of NA were characterised and quantified on one component of the complex synaptic response, the fast excitatory postsynaptic potential. The effect of NA was mimicked by the alpha 2 agonist UK 14,304 and blocked by the alpha 2 antagonist yohimbine. It is concluded that NA can inhibit via an alpha 2 receptor-mediated action synaptic responses in the superficial layers of the EC.
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Noradrenaline reduces synaptic responses in normal and Tottering Mouse entorhinal cortex via alpha 2 receptors.
Neuroscience letters, 1994Co-Authors: Etienne Pralong, P.j. MagistrettiAbstract:The effects of noradrenaline (NA) on synaptic responses in layer II of the entorhinal cortex (EC) were studied in normal and spontaneously epileptic mutant mice Tottering using intracellular recording in a slice preparation. Neither the membrane properties of neurones nor the responses to NA differed between normal and Tottering mice. NA (50 microM) hyperpolarized most (29/54) of the neurones via alpha 2 adrenergic receptors. Synaptic responses of EC neurones were complex. NA (10-100 microM) reduced all the components of the synaptic response in a concentration-dependent and reversible manner. The pharmacological properties of the inhibitory effect of NA were characterised and quantified on one component of the complex synaptic response, the fast excitatory postsynaptic potential. The effect of NA was mimicked by the alpha 2 agonist UK 14,304 and blocked by the alpha 2 antagonist yohimbine. It is concluded that NA can inhibit via an alpha 2 receptor-mediated action synaptic responses in the superficial layers of the EC.
Daniel B. Campbell - One of the best experts on this subject based on the ideXlab platform.
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Regulation of tyrosine hydroxylase expression in Tottering Mouse Purkinje cells.
Neurotoxicity research, 2003Co-Authors: Brandy E. Fureman, Daniel B. Campbell, Ellen J. HessAbstract:Tottering (tg) mice inherit a missense mutation in the Alpha1A subunit of P/Q-type calcium channels. This mutation results in an increased density of L-type calcium channels in the cerebellum and abnormal regulation of tyrosine hydroxylase (TH) gene expression in a subset of cerebellar Purkinje cells, a cell type that does not normally express TH. The behavioral phenotype includes attacks of dyskinesia, which can be blocked by L-type calcium channel antagonists. To test the hypothesis that cerebellar TH mRNA expression can be manipulated in vivo by L-type calcium channel blockade, control and Tottering mice were chronically treated with the L-type calcium channel antagonist nimodipine. Chronic nimodipine treatment significantly reduced the expression of TH mRNA in Tottering Mouse Purkinje cells. This effect was observed without altering the increased density of L-type calcium channels in Tottering Mouse cerebella. Chronic nimodipine treatment had no effect on TH mRNA expression in Tottering Mouse catecholaminergic neurons, including those of the locus coeruleus and substantia nigra. However, a small reduction in TH mRNA expression in the substantia nigra of control mice was observed after drug treatment. These data suggest that the abnormal expression of TH in Tottering Mouse Purkinje cells is regulated by Purkinje cell excitability.
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Regulation of tyrosine hydroxylase expression inTottering Mouse Purkinje cells
Neurotoxicity Research, 2003Co-Authors: Brandy E. Fureman, Daniel B. Campbell, Ellen J. HessAbstract:Tottering ( tg ) mice inherit a missense mutation in the α_1A subunit of P/Q-type calcium channels. This mutation results in an increased density of L-type calcium channels in the cerebellum and abnormal regulation of tyrosine hydroxylase (TH) gene expression in a subset of cerebellar Purkinje cells, a cell type that does not normally express TH. The behavioral phenotype includes attacks of dyskinesia, which can be blocked by L-type calcium channel antagonists. To test the hypothesis that cerebellar TH mRNA expression can be manipulated in vivo by L-type calcium channel blockade, control and Tottering mice were chronically treated with the L-type calcium channel antagonist nimodipine. Chronic nimodipine treatment significantly reduced the expression of TH mRNA in Tottering Mouse Purkinje cells. This effect was observed without altering the increased density of L-type calcium channels in Tottering Mouse cerebella. Chronic nimodipine treatment had no effect on TH mRNA expression in Tottering Mouse catecholaminergic neurons, including those of the locus coeruleus and substantia nigra. However, a small reduction in TH mRNA expression in the substantia nigra of control mice was observed after drug treatment. These data suggest that the abnormal expression of TH in Tottering Mouse Purkinje cells is regulated by Purkinje cell excitability.
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L-Type Calcium Channels Contribute to the Tottering Mouse Dystonic Episodes
Molecular pharmacology, 1999Co-Authors: Daniel B. Campbell, Ellen J. HessAbstract:Tottering mice inherit a recessive mutation of the calcium channel alpha1A subunit that causes ataxia, polyspike discharges, and intermittent dystonic episodes. The calcium channel alpha1A subunit gene encodes the pore-forming protein of P/Q-type voltage-dependent calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons with moderate expression in hippocampus and inferior colliculus. Because calcium misregulation likely underlies the Tottering Mouse phenotype, calcium channel blockers were tested for their ability to block the motor episodes. Pharmacologic agents that specifically block L-type voltage-dependent calcium channels, but not P/Q-type calcium channels, prevented the inducible dystonia of Tottering mutant mice. Specifically, the dihydropyridines nimodipine, nifedipine, and nitrendipine, the benzothiazepine diltiazem, and the phenylalkylamine verapamil all prevented restraint-induced Tottering Mouse motor episodes. Conversely, the L-type calcium channel agonist Bay K8644 induced stereotypic Tottering Mouse dystonic at concentrations significantly below those required to induce seizures in control mice. In situ hybridization demonstrated that L-type calcium channel alpha1C subunit mRNA expression was up-regulated in the Purkinje cells of Tottering mice. Radioligand binding with [3H]nitrendipine also revealed a significant increase in the density of L-type calcium channels in Tottering Mouse cerebellum. These data suggest that although a P/Q-type calcium channel mutation is the primary defect in Tottering mice, L-type calcium channels may contribute to the generation of the intermittent dystonia observed in these mice. The susceptibility of L-type calcium channels to voltage-dependent facilitation may promote this abnormal motor phenotype.
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Tottering Mouse motor dysfunction is abolished on the Purkinje cell degeneration (pcd) mutant background.
Experimental neurology, 1999Co-Authors: Daniel B. Campbell, Jesse B. North, Ellen J. HessAbstract:Tottering (tg) mice inherit a recessive mutation of the calcium channel alpha 1A subunit gene, which encodes the pore-forming protein of P/Q-type voltage-sensitive calcium channels and is predominantly expressed in cerebellar granule and Purkinje neurons. The phenotypic consequences of the Tottering mutation include ataxia, polyspike discharges, and an intermittent motor dysfunction best described as paroxysmal dystonia. These dystonic episodes induce c-fos mRNA expression in the cerebellar circuitry, including cerebellar granule and Purkinje neurons, deep cerebellar nuclei, and the postsynaptic targets of the deep nuclei. Cellular abnormalities associated with the mutation include hyperarborization of brainstem nucleus locus ceruleus axons and abnormal expression of L-type calcium channels in cerebellar Purkinje cells. Here, the role of these two distinct neural pathways in the expression of Tottering Mouse intermittent dystonia was assessed. Lesion of locus ceruleus axons with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzyl-amine (DSP-4) did not affect the frequency of Tottering Mouse dystonic episodes. In contrast, removal of cerebellar Purkinje cells with the Purkinje cell degeneration (pcd) mutation by generation of tg/tg; pcd/pcd double mutant mice completely eliminated Tottering Mouse dystonia. Further, the c-fos expression pattern of tg/tg; pcd/pcd double mutants following restraint was indistinguishable from that of wild-type mice, suggesting that the pcd lesion eliminated an essential link in this abnormal neural network. These data suggest that the cerebellar cortex, where the mutant gene is abundantly expressed, contributes to the expression of Tottering Mouse dystonic episodes.
Brandy E. Fureman - One of the best experts on this subject based on the ideXlab platform.
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Regulation of tyrosine hydroxylase expression in Tottering Mouse Purkinje cells.
Neurotoxicity research, 2003Co-Authors: Brandy E. Fureman, Daniel B. Campbell, Ellen J. HessAbstract:Tottering (tg) mice inherit a missense mutation in the Alpha1A subunit of P/Q-type calcium channels. This mutation results in an increased density of L-type calcium channels in the cerebellum and abnormal regulation of tyrosine hydroxylase (TH) gene expression in a subset of cerebellar Purkinje cells, a cell type that does not normally express TH. The behavioral phenotype includes attacks of dyskinesia, which can be blocked by L-type calcium channel antagonists. To test the hypothesis that cerebellar TH mRNA expression can be manipulated in vivo by L-type calcium channel blockade, control and Tottering mice were chronically treated with the L-type calcium channel antagonist nimodipine. Chronic nimodipine treatment significantly reduced the expression of TH mRNA in Tottering Mouse Purkinje cells. This effect was observed without altering the increased density of L-type calcium channels in Tottering Mouse cerebella. Chronic nimodipine treatment had no effect on TH mRNA expression in Tottering Mouse catecholaminergic neurons, including those of the locus coeruleus and substantia nigra. However, a small reduction in TH mRNA expression in the substantia nigra of control mice was observed after drug treatment. These data suggest that the abnormal expression of TH in Tottering Mouse Purkinje cells is regulated by Purkinje cell excitability.
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Regulation of tyrosine hydroxylase expression inTottering Mouse Purkinje cells
Neurotoxicity Research, 2003Co-Authors: Brandy E. Fureman, Daniel B. Campbell, Ellen J. HessAbstract:Tottering ( tg ) mice inherit a missense mutation in the α_1A subunit of P/Q-type calcium channels. This mutation results in an increased density of L-type calcium channels in the cerebellum and abnormal regulation of tyrosine hydroxylase (TH) gene expression in a subset of cerebellar Purkinje cells, a cell type that does not normally express TH. The behavioral phenotype includes attacks of dyskinesia, which can be blocked by L-type calcium channel antagonists. To test the hypothesis that cerebellar TH mRNA expression can be manipulated in vivo by L-type calcium channel blockade, control and Tottering mice were chronically treated with the L-type calcium channel antagonist nimodipine. Chronic nimodipine treatment significantly reduced the expression of TH mRNA in Tottering Mouse Purkinje cells. This effect was observed without altering the increased density of L-type calcium channels in Tottering Mouse cerebella. Chronic nimodipine treatment had no effect on TH mRNA expression in Tottering Mouse catecholaminergic neurons, including those of the locus coeruleus and substantia nigra. However, a small reduction in TH mRNA expression in the substantia nigra of control mice was observed after drug treatment. These data suggest that the abnormal expression of TH in Tottering Mouse Purkinje cells is regulated by Purkinje cell excitability.
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Triggers of paroxysmal dyskinesia in the calcium channel Mouse mutant Tottering.
Pharmacology biochemistry and behavior, 2002Co-Authors: Brandy E. Fureman, Hyder A. Jinnah, Ellen J. HessAbstract:Mutations in ion channels, or channelopathies, often lead to neurological disorders in which normal behavior is interrupted by attacks of debilitating symptoms such as pain, weakness or abnormal motor control. Attacks are often precipitated by similar stimuli, including stress, caffeine, ethanol, exercise or fatigue. The Tottering Mouse inherits a mutation in P/Q-type calcium channels and reliably exhibits attacks of abnormal movements, or dyskinesia. To determine if this Mouse mutant is an appropriate model to study episodic neurological disorders, Tottering mice were exposed to different environmental conditions or drugs known to precipitate attacks in humans. Stress, caffeine and ethanol all reliably induced attacks in Tottering mice. Since calcium influx has previously been implicated in stress-induced Tottering Mouse attacks, the L-type calcium channel antagonist, nimodipine, and the NMDA receptor antagonist, MK 801, were tested for their ability to prevent attacks caused by caffeine or ethanol administration. Nimodipine blocked both caffeine- and ethanol-induced attacks, while MK 801 was effective against stress- and caffeine-induced attacks. These results support a common role for excess neuronal excitability and increased calcium influx in attacks triggered by diverse agents. Together, these results suggest that the Tottering Mouse is a novel model to investigate triggers of episodic neurological disorders.