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. 2022 Jul;179(14):3754-3777.
doi: 10.1111/bph.15818. Epub 2022 Mar 15.

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

Guan-Hsun Wang  1 , Ai-Yu Chuang  2 , Yi-Chen Lai  2 , Hsin-I Chen  2 , Shu-Wei Hsueh  3 , Ya-Chin Yang  2   3   4   5
Affiliations

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

Guan-Hsun Wang et al. Br J Pharmacol. 2022 Jul.

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 KV 1.4 and post-synaptic KV 4.3 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.

Keywords: Kv1.4 channels; Kv4.3 channels; NS-5806; antiepileptic drug; brain rhythm regulation; epileptogenesis; glutamatergic transmission; neural network oscillations; voltage-gated A-type K+ channels.

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References

REFERENCES

    1. Alexander, S. P., Mathie, A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., & Southan, C. (2021). The concise guide to pharmacology 2021/22: Ion channels. British Journal of Pharmacology, 178, S157-S245. https://doi.org/10.1111/bph.15539
    1. Anderson, N. J., Slough, S., & Watson, W. P. (2006). In vivo characterisation of the small-conductance KCa (SK) channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a potential anticonvulsant. European Journal of Pharmacology, 546, 48-53. https://doi.org/10.1016/j.ejphar.2006.07.007
    1. Aroniadou-Anderjaska, V., Fritsch, B., Qashu, F., & Braga, M. F. (2008). Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy. Epilepsy Research, 78, 102-116. https://doi.org/10.1016/j.eplepsyres.2007.11.011
    1. Arshad, M. N., & Naegele, J. R. (2020). Induction of temporal lobe epilepsy in mice with pilocarpine. Bio-Protocol, 10, e3533. https://doi.org/10.21769/BioProtoc.3533
    1. Banerjee, J., Dixit, A. B., Tripathi, M., Sarkar, C., Gupta, Y. K., & Chandra, P. S. (2015). Enhanced endogenous activation of NMDA receptors in pyramidal neurons of hippocampal tissues from patients with mesial temporal lobe epilepsy: A mechanism of hyper excitation. Epilepsy Research, 117, 11-16. https://doi.org/10.1016/j.eplepsyres.2015.08.007

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