Loss of Navβ4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance

Ransdell, Joseph L.; Dranoff, Edward; Lau, Brandon; Lo, Wan‐Lin; Donermeyer, David L.; Allen, Paul M.; Nerbonne, Jeanne M.

doi:10.1016/j.celrep.2017.07.072

Cited by 19 publications

(16 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The decay time constant of the P7–14 group was significantly shorter than that of the P0–6 group. Thus, I NaR inactivates more rapidly in P7–14 group neurons, based on the mechanisms of inactivation of sodium channels (Grieco, Afshari, & Raman, ; Ransdell et al, ). Inactivation of I NaR is attributed to the Nav1.6 α subunit, and burst behavior with high‐frequency spikes in Mes V neurons is associated with expression of the Nav 1.6 isoform (Do & Bean, ; Grieco & Raman, ; Raman & Bean, ).…”

Section: Discussionmentioning

confidence: 99%

“…The membrane potential slowly depolarizes, and subthreshold oscillations are reinitiated and give rise to burst onset during the interburst period. For this neural behavior, recovery from slow inactivation of I NaP , not I NaR , most likely is the important mechanism (Enomoto et al, ; Wu et al, ) because I NaR can be activated from open channel block of the transient Na channel during firing (Grieco et al, ; Ransdell et al, ). We did not examine the development of slow inactivation of the sodium current in Mes V neurons in the present study.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Development of resurgent and persistent sodium currents in mesencephalic trigeminal neurons

Enomoto

Seki

Tanaka

et al. 2017

J of Neuroscience Research

View full text Add to dashboard Cite

Sodium channels play multiple roles in the formation of neural membrane properties in mesencephalic trigeminal (Mes V) neurons and in other neural systems. Mes V neurons exhibit conditional robust high-frequency spike discharges. As previously reported, resurgent and persistent sodium currents (I and I , respectively) may carry small currents at subthreshold voltages that contribute to generation of spike firing. These currents play an important role in maintaining and allowing high-frequency spike discharge during a burst. In the present study, we investigated the developmental changes in tetrodotoxin-sensitive I and I underlying high-frequency spike discharges in Mes V neurons. Whole-cell patch-clamp recordings showed that both current densities increased one and a half times from postnatal day (P) 0-6 neurons to P7-14 neurons. Although these neurons do not exhibit subthreshold oscillations or burst discharges with high-frequency firing, I and I do exist in Mes V neurons at P0-6. When the spike frequency at rheobase was examined in firing Mes V neurons, the developmental change in firing frequency among P7-14 neurons was significant. I and I density at -40 mV also increased significantly among P7-14 neurons. The change to an increase in excitability in the P7-14 group could result from this quantitative change in I In neurons older than P7 that exhibit repetitive firing, quantitative increases in I and I density may be major factors that facilitate and promote high-frequency firing as a function of age in Mes V neurons.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Development of resurgent and persistent sodium currents in mesencephalic trigeminal neurons

Enomoto

Seki

Tanaka

et al. 2017

J of Neuroscience Research

View full text Add to dashboard Cite

show abstract

“…Then, a 2 ms repolarization of Ϫ60 mV was applied to keep the distal Na ϩ channels inactivated and to allow partially activated proximal Na ϩ channels to deactivate. Finally, the third pulse (ranging from Ϫ75 to Ϫ20 mV) was used to measure fast transient Na ϩ currents originating from wellclamped proximal Na ϩ channels (Milescu et al, 2010;Bosch et al, 2015;Ransdell et al, 2017). The conductance ( G) of the fast transient Na ϩ currents was obtained by dividing the peak amplitude of recorded Na ϩ currents (I Na ) by the electrochemical driving force:…”

Section: Methodsmentioning

confidence: 99%

“…half is the midpoint of activation and k is the slope factor. When we examined the voltage dependence of the steady-state inactivation of the fast Na ϩ currents, we could not use the pre-pulse protocol above (Milescu et al, 2010;Bosch et al, 2015;Ransdell et al, 2017). Therefore, 50 nM TTX was always included in the modified extracellular ACSF to reduce Na ϩ current amplitudes and to minimize voltage-clamp errors.…”

Section: Methodsmentioning

confidence: 99%

“…However, there was no difference in the voltage dependence of the transient Na ϩ current activation, measured with a modified three-step voltage protocol ( Fig. 5C; see Materials and Methods;Milescu et al, 2010;Bosch et al, 2015;Ransdell et al, 2017), between WT and ARF4 ϩ/Ϫ /ARF5 Ϫ/Ϫ PCs (Fig. 5D).…”

Section: Class II Arf-deficient Mice Exhibit Movement-related Abnormamentioning

confidence: 96%

See 1 more Smart Citation

Deletion of Class II ADP-Ribosylation Factors in Mice Causes Tremor by the Nav1.6 Loss in Cerebellar Purkinje Cell Axon Initial Segments

Hosoi¹,

Shibasaki

Hosono

et al. 2019

J. Neurosci.

View full text Add to dashboard Cite

ADP-ribosylation factors (ARFs) are a family of small monomeric GTPases comprising six members categorized into three classes: class I (ARF1, 2, and 3), class II (ARF4 and 5), and class III (ARF6). In contrast to class I and III ARFs, which are the key regulators in vesicular membrane trafficking, the cellular function of class II ARFs remains unclear. In the present study, we generated class II ARF-deficient mice and found that ARF4 ϩ/Ϫ /ARF5 Ϫ/Ϫ mice exhibited essential tremor (ET)-like behaviors. In vivo electrophysiological recordings revealed that ARF4 ϩ/Ϫ /ARF5 Ϫ/Ϫ mice of both sexes exhibited abnormal brain activity when moving, raising the possibility of abnormal cerebellar excitability. Slice patch-clamp experiments demonstrated the reduced excitability of the cerebellar Purkinje cells (PCs) in ARF4 ϩ/Ϫ /ARF5 Ϫ/Ϫ mice. Immunohistochemical and electrophysiological analyses revealed a severe and selective decrease of poreforming voltage-dependent Na ϩ channel subunit Nav1.6, important for maintaining repetitive action potential firing, in the axon initial segment (AIS) of PCs. Importantly, this decrease in Nav1.6 protein localized in the AIS and the consequent tremors in ARF4 ϩ/Ϫ / ARF5 Ϫ/Ϫ mice could be alleviated by the PC-specific expression of ARF5 using adeno-associated virus vectors. Together, our data demonstrate that the decreased expression of the class II ARF proteins in ARF4 ϩ/Ϫ /ARF5 Ϫ/Ϫ mice, leading to a haploinsufficiency of ARF4 in the absence of ARF5, impairs the localization of Nav1.6 to the AIS and hence reduces the membrane excitability in PCs, resulting in the ET-like movement disorder. We suggest that class II ARFs function in localizing specific proteins, such as Nav1.6, to the AIS.

show abstract

Development of Physiological Activity in the Cerebellum

Jayabal

Watt

2021

Handbook of the Cerebellum and Cerebellar Disorders

View full text Add to dashboard Cite

One remarkable aspect of cerebellar development is that intrinsic physiological activity of several neuronal cell types, including Purkinje cells, can be observed throughout a large portion of the developmental window. Although ion channels primarily drive this intrinsic activity, it can also be influenced by other cellular properties and inputs, including synaptic and neuromodulatory inputs, calcium buffers, and others. Many of the factors that drive or influence intrinsic activity are expressed in a tightly regulated manner during the development of the cerebellum. Here, we review how the ion channels, calcium buffers, synapses, and neuromodulators that are differentially expressed during development give

show abstract

Loss of Navβ4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance

Cited by 19 publications

References 0 publications

Development of resurgent and persistent sodium currents in mesencephalic trigeminal neurons

Development of resurgent and persistent sodium currents in mesencephalic trigeminal neurons

Deletion of Class II ADP-Ribosylation Factors in Mice Causes Tremor by the Nav1.6 Loss in Cerebellar Purkinje Cell Axon Initial Segments

Development of Physiological Activity in the Cerebellum

Contact Info

Product

Resources

About