Action potential broadening in a presynaptic channelopathy.

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

doi:10.1038/ncomms12102

Rahima Begum, Yamina Bakiri + Show 2 more

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https://doi.org/10.1038/ncomms12102

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Abstract

Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca2+ influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

Highlights

Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission
The Kcna1V408A/ þ mouse shows an increase in spontaneous inhibitory postsynaptic currents (IPSCs) frequency in Purkinje cells relative to wild-type littermates[18], but how this relates to action potential-dependent GABA release from basket cell terminals is unclear
The present study reveals a major role of Kv1.1 channels in action potential repolarization at basket cell terminals, which was not apparent when recording from somata

Summary

Introduction

Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. The Kcna1V408A/ þ mouse shows an increase in spontaneous IPSC frequency in Purkinje cells relative to wild-type littermates[18], but how this relates to action potential-dependent GABA release from basket cell terminals is unclear. We first characterized presynaptic action potentials at cerebellar basket cell terminals of wild-type mice, and compared the effects of pharmacological and genetic manipulations of Kv1.1 on presynaptic spike shape, action potential Ca2 þ influx, and GABAergic inhibition of Purkinje cells

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