Sodium Currents in Subthalamic Nucleus Neurons From Na<sub>v</sub>1.6-Null Mice

H., Michael Tri; Bean, Bruce P.

doi:10.1152/jn.00186.2004

Cited by 79 publications

(77 citation statements)

References 41 publications

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“…Based on the nearly complete elimination of resurgent currents in Purkinje neurons of Scn8a-null mice (Raman and Bean, 1999a,b), it had been thought that Na V 1.6 is unique in conducting resurgent sodium current, but recent studies of subthalamic neurons of Scn8a-null mice revealed that other sodium channels are also involved (Do and Bean, 2004). The reduction of resurgent sodium current in Purkinje neurons of Na V 1.1 HET and KO mice provides the first evidence for a role of a specific sodium channel subtype other than Na V 1.6 in generation of resurgent sodium currents in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Resurgent sodium current, a component of sodium current that flows transiently on repolarization of the cell, has been identified in cerebellar Purkinje neurons and other central neurons (Raman and Bean, 1997; Afshari et al, 2004;Do and Bean, 2004). Like the persistent sodium current, resurgent current has been implicated in promoting fast repetitive neuronal firing in these neurons Bean, 1997, 1999a; by accelerating depolarization toward threshold between action potentials (Raman and Bean, 1999a).…”

Section: Reduced Resurgent Sodium Current In Purkinje Neurons Of Het mentioning

confidence: 99%

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Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Kalume¹,

Yu²,

Westenbroek³

et al. 2007

J. Neurosci.

238

251

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Loss-of-function mutations of Na V 1.1 channels cause severe myoclonic epilepsy in infancy (SMEI), which is accompanied by severe ataxia that contributes substantially to functional impairment and premature deaths. Mutant mice lacking Na V 1.1 channels provide a genetic model for SMEI, exhibiting severe seizures and premature death on postnatal day 15. Behavioral assessment indicated severe motor deficits in mutant mice, including irregularity of stride length during locomotion, impaired motor reflexes in grasping, and mild tremor in limbs when immobile, consistent with cerebellar dysfunction. Immunohistochemical studies showed that Na V 1.1 and Na V 1.6 channels are the primary sodium channel isoforms expressed in cerebellar Purkinje neurons. The amplitudes of whole-cell peak, persistent, and resurgent sodium currents in Purkinje neurons were reduced by 58 -69%, without detectable changes in the kinetics or voltage dependence of channel activation or inactivation. Nonlinear loss of sodium current in Purkinje neurons from heterozygous and homozygous mutant animals suggested partial compensatory upregulation of Na V 1.6 channel activity. Current-clamp recordings revealed that the firing rates of Purkinje neurons from mutant mice were substantially reduced, with no effect on threshold for action potential generation. Our results show that Na V 1.1 channels play a crucial role in the excitability of cerebellar Purkinje neurons, with major contributions to peak, persistent, and resurgent forms of sodium current and to sustained action potential firing. Loss of these channels in Purkinje neurons of mutant mice and SMEI patients may be sufficient to cause their ataxia and related functional deficits.

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Section: Discussionmentioning

confidence: 99%

Section: Reduced Resurgent Sodium Current In Purkinje Neurons Of Het mentioning

confidence: 99%

Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Kalume¹,

Yu²,

Westenbroek³

et al. 2007

J. Neurosci.

238

251

View full text Add to dashboard Cite

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“…Furthermore, a recent comparison of the same neurons and Purkinje neurons (46,47) suggests that slow inactivation or other putative sodium currents may contribute to the intriguing roles of resurgent and persistent currents. Since our study shows that Cn2 not only has sharp channel selectivity and binding stability for the Na v 1.6 isoform but also blocks firing in Purkinje neurons at appropriate concentrations, we propose using Cn2 as a leading compound for the study of Parkinson disease.…”

Section: Discussionmentioning

confidence: 99%

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

Schiavon

Sacco

Cassulini

et al. 2006

Journal of Biological Chemistry

109

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Resurgent currents are functionally crucial in sustaining the high frequency firing of cerebellar Purkinje neurons expressing Na v 1.6 channels. ␤-Scorpion toxins, such as CssIV, induce a left shift in the voltage-dependent activation of Na v 1.2 channels by "trapping" the IIS4 voltage sensor segment. We found that the dangerous Cn2 ␤-scorpion peptide induces both the left shift voltage-dependent activation and a transient resurgent current only in human Na v 1.6 channels (among 1.1-1.7), whereas CssIV did not induce the resurgent current. Cn2 also produced both actions in mouse Purkinje cells. These findings suggest that only distinct ␤-toxins produce resurgent currents. We suggest that the novel and unique selectivity of Cn2 could make it a model drug to replace deep brain stimulation of the subthalamic nucleus in patients with Parkinson disease.

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“…Li and Bennett (2003) demonstrated inward currents seen during slow ramp depolarizations that were insensitive to dihydropridines and blocked by TTX. It is known that some Na V subtypes mediate sodium currents with slower time constants of inactivation (Do and Bean, 2004), but the specific subtype of Na V channel which may underlie a Na-PIC is not yet clear. These currents are unlikely to be "persistent" or non-inactivating per se and are more likely to be slowly inactivating (Doand Bean, 2004).…”

Section: The Role Of Motoneuron Dendrites In Repetitive Firingmentioning

confidence: 99%

Beginning at the end: Repetitive firing properties in the final common pathway

Brownstone

2006

Progress in Neurobiology

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Since the early 20th century, it has been recognized that motoneurons must fire repetitive trains of action potentials to produce muscle contraction. In 1932, Sir John Eccles, together with Hebbel Hoff, found that action potential spike trains in motor axons were produced by "rhythmic centres", which were within the motoneurons themselves. Two decades later, Eccles attended a Cold Spring Harbor Symposium in NY, USA entitled "The Neuron". Two of the many notable presentations at this symposium were juxtaposed: one by Eccles from the University of Otago, Dunedin, NZL, and the other by J. Walter Woodbury and Harry Patton from the University of Washington, Seattle, USA. Both presentations included data obtained using sharp microelectrodes to study the intracellularly recorded potentials of cat motoneurons. In this review, I discuss some of the events leading up to and surrounding this jointly accomplished advance and proceed to discussion of subsequent studies over 5+ decades that have made use of intracellular recordings from motoneurons to study their repetitive firing behavior. This begins with early descriptions of primary and secondary range firing, and continues to the discovery of dendritic persistent inward currents and their relation to plateau potentials, synaptic amplification, and motoneuronal firing. Following a brief description of the possible mechanisms underlying spike frequency adaptation, I discuss the modulation of repetitive firing properties during various motor behaviors. It has become increasingly clear that the central nervous system has exquisite control of the repetitive firing of motoneurons. Eccles' work laid the foundation for the present-day study of these processes.

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Sodium Currents in Subthalamic Nucleus Neurons From Na_v1.6-Null Mice

Abstract: Do, Michael Tri H. and Bruce P. Bean. Sodium currents in subthalamic nucleus neurons from Na v 1.6-null mice.

Cited by 79 publications

References 41 publications

Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

Beginning at the end: Repetitive firing properties in the final common pathway

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Sodium Currents in Subthalamic Nucleus Neurons From Nav1.6-Null Mice

Abstract: Do, Michael Tri H. and Bruce P. Bean. Sodium currents in subthalamic nucleus neurons from Na v 1.6-null mice.

Cited by 79 publications

References 41 publications

Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Resurgent Current and Voltage Sensor Trapping Enhanced Activation by a β-Scorpion Toxin Solely in Nav1.6 Channel

Beginning at the end: Repetitive firing properties in the final common pathway

Contact Info

Product

Resources

About

Sodium Currents in Subthalamic Nucleus Neurons From Na_v1.6-Null Mice

Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

Reduced Sodium Current in Purkinje Neurons from Na_V1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy