Pre-synaptic and post-synaptic A-type K+ channels regulate glutamatergic transmission and switching of the network into epileptiform oscillations

Guan Hsun Wang, Ai Yu Chuang, Yi Chen Lai, Hsin I. Chen, Shu Wei Hsueh, Ya Chin Yang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

2 Scopus citations

Abstract

Background and Purpose: Anticonvulsants targeting K+ channels have not been clinically available, although neuronal hyperexcitability in seizures could be suppressed by activation of K+ channels. Voltage-gated A-type K+ channel (A-channel) inhibitors may be prescribed for diseases of neuromuscular junction but could cause seizures. Consistently, genetic loss of function of A-channels may also cause seizures. It is unclear why inhibition of A-channels, compared with other types of K+ channels, is particularly prone to seizure induction. This hinders the development of relevant therapeutic interventions. Experimental Approach: Mechanisms underlying epileptogenesis with A-channel inhibition and antiepileptic actions of A-channel activation were investigated with electrophysiological, pharmacological, optogenetic, and behavioral approaches. Key Results: Pre-synaptic KV1.4 and post-synaptic KV4.3 A-channels act synergistically to gate glutamatergic transmission and control rhythmogenesis in the amygdala. The interconnected neurons set into the oscillatory mode by A-channel inhibition would reverberate with regular paces and the same top frequency, demonstrating a spatio-temporally well-orchestrated system with built-in oscillatory rhythms normally curbed by A-channels. Accordingly, selective over-excitation of glutamatergic neurons or inhibition of A-channels can induce behavioural seizures, which may be ameliorated by A-channel activators (e.g. NS-5806) or AMPA receptor antagonists (e.g. perampanel). Conclusion and Implications: Trans-synaptic voltage-dependent A-channels serve as a biophysical-biochemical transducer responsible for a novel form of synaptic plasticity. Such a network-level switch into and out of the oscillatory mode may underlie a wide scope of telencephalic information processing or, at its extreme, epileptic seizures. A-channels thus constitute a potential target of antiepileptic therapy.

Original languageEnglish
Pages (from-to)3754-3777
Number of pages24
JournalBritish Journal of Pharmacology
Volume179
Issue number14
DOIs
StatePublished - 07 2022

Bibliographical note

Publisher Copyright:
© 2022 The British Pharmacological Society.

Keywords

  • K1.4 channels
  • K4.3 channels
  • NS-5806
  • antiepileptic drug
  • brain rhythm regulation
  • epileptogenesis
  • glutamatergic transmission
  • neural network oscillations
  • voltage-gated A-type K channels

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