| First Author | Wang GH | Year | 2022 |
| Journal | Br J Pharmacol | Volume | 179 |
| Issue | 14 | Pages | 3754-3777 |
| PubMed ID | 35170022 | Mgi Jnum | J:350226 |
| Mgi Id | MGI:7661246 | Doi | 10.1111/bph.15818 |
| Citation | Wang GH, et al. (2022) 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 |
| abstractText | 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 K(V) 1.4 and post-synaptic K(V) 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. |
