Pre-synaptic and post-synaptic A-type K+ channels regulate glutamatergic transmission and switching of the network into epileptiform oscillations.
Br J Pharmacol
; 179(14): 3754-3777, 2022 07.
Article
em En
| MEDLINE
| ID: mdl-35170022
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. EXPERIMENTALAPPROACH:
Mechanisms underlying epileptogenesis with A-channel inhibition and antiepileptic actions of A-channel activation were investigated with electrophysiological, pharmacological, optogenetic, and behavioral approaches. KEYRESULTS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Convulsões
/
Anticonvulsivantes
Limite:
Humans
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Taiwan