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Voltage\u2010gated A\u2010type K<jats:sup>+<\/jats:sup> channel (A\u2010channel) inhibitors may be prescribed for diseases of neuromuscular junction but could cause seizures. Consistently, genetic loss of function of A\u2010channels may also cause seizures. It is unclear why inhibition of A\u2010channels, compared with other types of K<jats:sup>+<\/jats:sup> channels, is particularly prone to seizure induction. This hinders the development of relevant therapeutic interventions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Mechanisms underlying epileptogenesis with A\u2010channel inhibition and antiepileptic actions of A\u2010channel activation were investigated with electrophysiological, pharmacological, optogenetic, and behavioral approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Pre\u2010synaptic K<jats:sub>V<\/jats:sub>1.4 and post\u2010synaptic K<jats:sub>V<\/jats:sub>4.3 A\u2010channels act synergistically to gate glutamatergic transmission and control rhythmogenesis in the amygdala. The interconnected neurons set into the oscillatory mode by A\u2010channel inhibition would reverberate with regular paces and the same top frequency, demonstrating a spatio\u2010temporally well\u2010orchestrated system with built\u2010in oscillatory rhythms normally curbed by A\u2010channels. Accordingly, selective over\u2010excitation of glutamatergic neurons or inhibition of A\u2010channels can induce behavioural seizures, which may be ameliorated by A\u2010channel activators (e.g. NS\u20105806) or AMPA receptor antagonists (e.g. perampanel).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Trans\u2010synaptic voltage\u2010dependent A\u2010channels serve as a biophysical\u2010biochemical transducer responsible for a novel form of synaptic plasticity. Such a network\u2010level switch into and out of the oscillatory mode may underlie a wide scope of telencephalic information processing or, at its extreme, epileptic seizures. A\u2010channels thus constitute a potential target of antiepileptic therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15818","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T01:59:47Z","timestamp":1644976787000},"page":"3754-3777","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Pre\u2010synaptic and post\u2010synaptic A\u2010type K<sup>+<\/sup> channels regulate glutamatergic transmission and switching of the network into epileptiform oscillations"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7112-1051","authenticated-orcid":false,"given":"Guan\u2010Hsun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology Chang Gung Memorial Hospital, Linkou Medical Center  Tao\u2010Yuan 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