Subcellular control of membrane excitability in the axon

Alpizar, Scott A; Cho, In Ha; Hoppa, Michael B.

doi:10.1016/j.conb.2019.01.020

Cited by 11 publications

(8 citation statements)

References 82 publications

(87 reference statements)

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“…However, the present results suggest that I h in fast is decreased relative to slow motor axons. This implies that regulation of expression of HCN channels, which generate I h , would be different in the soma versus axon, a suggestion that is in keeping with current evidence [1].…”

Section: Functional Implications Of Differences In I Hsupporting

confidence: 77%

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just I_h

Bell¹,

Lorenz

Jones

2019

Preprint

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Objective:The objective was to determine if choice of anaesthetic confounded previous conclusions about the differences in nerve excitability indices between fast and slow motor axons.Methodology: Nerve excitability of the rat sciatic nerve was tested while measuring responses of motor axons innervating the slow-twitch soleus (SOL) and fast-twitch tibialis anterior (TA) muscles. The experiments were conducted with sodium pentobarbital (SP) anaesthetic and compared to previous results that used ketamine-xylazine (KX).Results and Conclusions: Previous conclusions about the differences in nerve excitability indices between TA and SOL motor axons using KX were corroborated and extended when experiments were done with SP. Nerve excitability indices sensitive to changes in hyperpolarization-activated inwardly rectifying cation current (I h ) indicated an increase in I h in SOL axons compared to TA axons (e.g. S3 (−100 %), t=7.949 (df=10),p <0.0001; TEh (90-100 ms), t=2.659 (df=20), p = 0.0145; hyperpolarizing I/V slope, t=4.308 (df=19), p = 0.0004). SOL axons also had a longer strengthduration time constant (t=3.35 (df=20), p = 0.0032) and a longer and larger magnitude relative refractory period (RRP (ms) t=3.53 (df=12), p = 0.0041; Refractoriness at 2 ms t=0.0055 (df=9), p = 0.0055).Anaesthetic choice affected many measures of peripheral nerve excitability with differences most apparent in tests of threshold electrotonus and recovery cycle. For example, recovery cycle with KX lacked a clear superexcitable and late subexcitable period. We conclude that KX had a confounding effect on nerve excitability results consistent with ischaemic depolarization. Results using SP revealed the full extent of differences in nerve excitability measures between putative slow and fast motor axons of the rat. These differences have important implications for the use of nerve excitability measures during processes such as ageing where it is believed that there is a selective loss of fast axons. New & NoteworthyNerve excitability testing is a tool used to provide insight into the properties of ion channels in peripheral nerves. It is used clinically to assess pathophysiology of motor axons. Researchers customarily think of motor axons as homogeneous; however, we demonstrate there are clear differences between f ast and slow axons in the rat. This is important for interpreting results with selective motor neuronopathy, like aging where f ast axons are at high risk of degeneration.

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Section: Functional Implications Of Differences In I Hsupporting

confidence: 77%

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just I_h

Bell¹,

Lorenz

Jones

2019

Preprint

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“…In comparing isoflurane inhibition of SV exocytosis in control vs. shRNA-treated Nav1.1 neurons (Figure 4), shRNA-mediated knockdown of Nav1.1 increased inhibition by isoflurane of SV exocytosis compared to untreated GABAergic/GAD2 + neurons, but had no effect on glutamatergic/GAD2neurons (GAD2 + : + shRNA 62.5%±19.0 vs. -shRNA 83.7±22.0%, p=0.013, t-test; glutamatergic/GAD2neurons: + shRNA 56.3%±18.4 vs -shRNA 64.5±8.5, p=0.17, unpaired t-test). This neuron subtype-specific effect is consistent with greater endogenous Nav1.1 expression in GABAergic interneurons (49).…”

Section: Knockdown Of Nav11 In Gabaergic Neurons Increases Anesthetisupporting

confidence: 66%

Differential inhibition of GABA release from mouse hippocampal interneuron subtypes by the volatile anesthetic isoflurane

Speigel

Hemmings

2020

Preprint

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General anesthesia is critical to modern medicine and animal research, but the cellular and molecular actions of general anesthetics on the central nervous system remain poorly understood. Volatile anesthetics such as isoflurane disrupt synaptic transmission and inhibit synaptic vesicle release in a neurotransmitter-selective manner. For example, GABA release from interneurons is less sensitive to isoflurane inhibition than are glutamate or dopamine release. Hippocampal and cortical interneuron subpopulations have diverse neurophysiological and synaptic properties, and their individual subtype-specific responses to isoflurane are unknown. We used live-cell optical imaging of exocytosis using fluorescent biosensors expressed in transgenic mouse hippocampal neuron cultures to delineate interneuron subtype-specific effects of isoflurane on synaptic vesicle exocytosis. We found that a clinically relevant concentration of isoflurane (0.5 mM) differentially modulated action potential-mediated exocytosis from GABAergic interneurons: parvalbumin-expressing interneurons were inhibited to 83.1±11.7% of control, whereas somatostatin-expressing and interneurons glutamatergic neurons were inhibited to 58.6±13.3% and 64.5±8.5% of control, respectively. The role of presynaptic voltage-gated sodium channel (Nav) subtype expression in determining isoflurane sensitivity was probed by overexpression or knockdown of specific Nav subtypes, which have distinct sensitivities to isoflurane and are differentially expressed between glutamatergic and GABAergic neurons. We found that the sensitivity of exocytosis to isoflurane was determined by the relative expression of Nav1.1 (associated with lower sensitivity) and Nav1.6 (associated with higher sensitivity). Thus the selective effects of isoflurane on synaptic vesicle exocytosis from hippocampal interneuron subtypes is determined by synaptic diversity in the relative expression of Nav1.1 and Nav1.6.Significance statementThe volatile anesthetic isoflurane inhibits hippocampal GABAergic interneuron synaptic vesicle exocytosis with differences in potency between interneuron subtypes. This neuron subtype-specific pharmacology derives in part from synaptic diversity in the expression of presynaptic voltage-gated sodium channels that have different sensitivities to anesthetic modulation of channel function. GABAergic interneurons are generally more resistant to the presynaptic effects of isoflurane owing to predominant Nav1.1 expression, whereas glutamatergic neurons are more sensitive owing to predominant Nav1.6 expression, which supports heterogenous pharmacologic effects on specific neural circuits.

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“…The intrinsic properties and unique firing signatures of neurons are in part mediated by the expression of different types of ionic channels and their functional modulation [1,2].…”

Section: Introductionmentioning

confidence: 99%

Voltage‐gated calcium channel nanodomains: molecular composition and function

Gandini

Zamponi

2021

The FEBS Journal

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Voltage-gated calcium (Ca V) channels and their regulation by proteins at the synaptic cleft play a critical role in neurotransmission. These interactions fine-tune the synaptic response through the regulation of Ca 2+ entry into the presynaptic terminal and trigger the fusion of vesicles filled with neurotransmitters and peptides. Regulation of Ca V channel intrinsic properties and their numbers at the active zones shape the timing and strength of synapses. Here, we provide an overview of a number of proteins reported to be part of Ca V channel nanodomains at the synaptic cleft and the repercussions of these interactions for Ca V channel trafficking, tethering at the active zone, and regulation of their biophysical properties. We summarize the current state of knowledge by which Ca V channels are regulated at presynaptic sites.

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Subcellular control of membrane excitability in the axon

Cited by 11 publications

References 82 publications

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just I_h

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just I_h

Differential inhibition of GABA release from mouse hippocampal interneuron subtypes by the volatile anesthetic isoflurane

Voltage‐gated calcium channel nanodomains: molecular composition and function

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Subcellular control of membrane excitability in the axon

Cited by 11 publications

References 82 publications

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just Ih

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just Ih

Differential inhibition of GABA release from mouse hippocampal interneuron subtypes by the volatile anesthetic isoflurane

Voltage‐gated calcium channel nanodomains: molecular composition and function

Contact Info

Product

Resources

About

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just I_h

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just I_h