Action potential broadening in a presynaptic channelopathy

Begum, Rahima; Bakiri, Yamina; Volynski, Kirill E.; Kullmann, Dimitri M.

doi:10.1038/ncomms12102

Cited by 66 publications

(65 citation statements)

References 56 publications

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“…The data thus fill a gap in the evidence that action potential width modulation by relatively brief subthreshold somatic depolarizations occurs in intact axons. At hippocampal mossy fiber synapses, presynaptic spike broadening leads to a proportional increase in Ca 2+ influx (31), and a similar principle underlies signaling at basket cell terminals in the cerebellar cortex (32). Assuming a Ca 2+ current cooperativity ∼2 (33, 34), the ∼12% analog spike broadening seen here (Fig.…”

Section: Discussionmentioning

confidence: 78%

“…These are most likely attributable to abnormal GABA release from cerebellar basket cells (29) and to motor axon hyperexcitability, respectively (40), both sites where Kv1.1 is especially abundantly expressed (20,21,40,41). Indeed, presynaptic spike broadening has been demonstrated at these terminals in the Kcna1 V408A/+ mouse (32). Nevertheless, epilepsy occurs in a high proportion of affected individuals (25,27), implying a role in circuit excitability in the forebrain.…”

Section: Discussionmentioning

confidence: 99%

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Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization

Vivekananda

Novák

Bello

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Although action potentials propagate along axons in an all-or-none manner, subthreshold membrane potential fluctuations at the soma affect neurotransmitter release from synaptic boutons. An important mechanism underlying analog-digital modulation is depolarizationmediated inactivation of presynaptic Kv1-family potassium channels, leading to action potential broadening and increased calcium influx. Previous studies have relied heavily on recordings from blebs formed after axon transection, which may exaggerate the passive propagation of somatic depolarization. We recorded instead from small boutons supplied by intact axons identified with scanning ion conductance microscopy in primary hippocampal cultures and asked how distinct potassium channels interact in determining the basal spike width and its modulation by subthreshold somatic depolarization. Pharmacological or genetic deletion of Kv1.1 broadened presynaptic spikes without preventing further prolongation by brief depolarizing somatic prepulses. A heterozygous mouse model of episodic ataxia type 1 harboring a dominant Kv1.1 mutation had a similar broadening effect on basal spike shape as deletion of Kv1.1; however, spike modulation by somatic prepulses was abolished. These results argue that the Kv1.1 subunit is not necessary for subthreshold modulation of spike width. However, a disease-associated mutant subunit prevents the interplay of analog and digital transmission, possibly by disrupting the normal stoichiometry of presynaptic potassium channels.channelopathy | synaptic transmission | potassium channel A lthough action potentials are generated at the axon initial segment in an all-or-none manner, synaptic transmission can be modulated by electrotonic propagation of subthreshold membrane depolarization from the soma (1-6). Inactivation of axonal Kv1-family channels contributes to "analog" signaling by broadening presynaptic action potentials (6-9). Investigations of presynaptic spike shape in small presynaptic boutons have relied heavily on extrapolation from recordings in blebs that form after axons have been transected (2,6,8,9). A potential pitfall of this method is that the ion channels present in blebs may not be representative of the normal complement of channels at an unperturbed bouton. A further difficulty is that the attenuation of voltage with distance from the soma is likely to be smaller than when recording from an intact axon. Indeed, classical cable theory predicts that steady-state somatic voltage should decrease by ∼63% at one length constant if the axon is represented by an infinite cable, but only by ∼35% if it is sealed at the same point (10). The discrepancy increases as the axon is made shorter: if the axon is cut at half a length constant, the attenuation of steady-state voltage at its termination is only ∼29% of that predicted for an infinite cable. Given that the length constant of unmyelinated axons in the CNS has been estimated in the range of 400-600 μm (1-3, 9, 11), this implies that the modulation of action potential shape...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization

Vivekananda

Novák

Bello

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In hippocampal pyramidal cells, DTX-sensitive currents mediated by channels that contain Kv1.2 are also regulated by electrical activity through Ca 2+ entry (Hyun et al, 2013). It has also been reported that cerebellar basket cells of heterozygotes that carry a mutation in Kv1.1, Kcna1 V408A/+ , have normal somatic action potentials but broadened action potentials at terminals that resulted in an increased release of GABA that was not compensated (Begum et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Genetic perturbations suggest a role of the resting potential in regulating the expression of the ion channels of the KCNA and HCN families in octopus cells of the ventral cochlear nucleus

Cao

Oertel

2017

Hearing Research

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Low-voltage-activated K+ (gKL) and hyperpolarization-activated mixed cation conductances (gh) mediate currents, IKL and Ih, through channels of the Kv1 (KCNA) and HCN families respectively and give auditory neurons the temporal precision required for signaling information about the onset, fine structure, and time of arrival of sounds. Being partially activated at rest, gKL and gh contribute to the resting potential and shape responses to even small subthreshold synaptic currents. Resting gKL and gh also affect the coupling of somatic depolarization with the generation of action potentials. To learn how these important conductances are regulated we have investigated how genetic perturbations affect their expression in octopus cells of the ventral cochlear nucleus (VCN). We report five new findings: First, the magnitude of gh and gKL varied over more than two-fold between wild type strains of mice. Second, average resting potentials are not different in different strains of mice even in the face of large differences in average gKL and gh. Third, IKL has two components, one being α-dendrotoxin (α-DTX)-sensitive and partially inactivating and the other being α-DTX-insensitive, tetraethylammonium (TEA)-sensitive, and non-inactivating. Fourth, the loss of Kv1.1 results in diminution of the α-DTX-sensitive IKL, and compensatory increased expression of an α-DTX-insensitive, tetraethylammonium (TEA)-sensitive IKL. Fifth, Ih and IKL are balanced at the resting potential in all wild type and mutant octopus cells even when resting potentials vary in individual cells over nearly 10 mV, indicating that the resting potential influences the expression of gh and gKL. The independence of resting potentials on gKL and gh shows that gKL and gh do not, over days or weeks, determine the resting potential but rather that the resting potential plays a role in regulating the magnitude of either or both gKL and gh.

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“…The study of functional properties of ion channels in the axon is only at its beginning. And the recent development of direct recordings from thin axons and presynaptic terminals (Novak et al, 2013; Kawaguchi and Sakaba, 2015; Begum et al, 2016; Rowan et al, 2016) together with the development of genetically-encoded voltage indicators (Hoppa et al, 2014) will certainly open new investigation opportunities about the role and function of ion channels in the presynaptic compartment.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Control of Neurotransmitter Release by Presynaptic Potential

Zbili

Rama

Debanne

2016

Front. Cell. Neurosci.

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Action potentials (APs) in the mammalian brain are thought to represent the smallest unit of information transmitted by neurons to their postsynaptic targets. According to this view, neuronal signaling is all-or-none or digital. Increasing evidence suggests, however, that subthreshold changes in presynaptic membrane potential before triggering the spike also determines spike-evoked release of neurotransmitter. We discuss here how analog changes in presynaptic voltage may regulate spike-evoked release of neurotransmitter through the modulation of biophysical state of voltage-gated potassium, calcium and sodium channels in the presynaptic compartment. The contribution of this regulation has been greatly underestimated and we discuss the impact for information processing in neuronal circuits.

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Action potential broadening in a presynaptic channelopathy

Cited by 66 publications

References 56 publications

Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization

Kv1.1 channelopathy abolishes presynaptic spike width modulation by subthreshold somatic depolarization

Genetic perturbations suggest a role of the resting potential in regulating the expression of the ion channels of the KCNA and HCN families in octopus cells of the ventral cochlear nucleus

Dynamic Control of Neurotransmitter Release by Presynaptic Potential

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