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<p>The mechanisms underlying the generation and termination of epileptic discharges remain incompletely understood. This study investigates the role of K<sub>Ca</sub>3.1 (KCNN4) channels in modulating epileptiform activity in the deep layers of the entorhinal cortex using two in vitro models: short-lasting late recurrent discharges (LRDs) and prolonged tonic–clonic seizure-like events (SLEs). Whole-cell patch-clamp recordings in rodent brain slices revealed that blocking K<sub>Ca</sub>3.1 channels with TRAM-34 increased neuronal excitability and firing frequency, enabling sustained firing at higher depolarizing currents. In the LRD model, TRAM-34 had no effect on the frequency or duration of spontaneously generated LRDs, likely due to the low intrinsic expression of K<sub>Ca</sub>3.1 channels in the entorhinal cortex. However, NS-309, a positive modulator of K<sub>Ca</sub>3.1 and SK channels, reduced LRD duration, while TRAM-34 prolonged LRDs induced by extracellular stimulation. In the SLE model, TRAM-34 increased SLE frequency and enhanced glutamatergic activity at SLE onset, indicating a more pronounced role of K<sub>Ca</sub>3.1 channels during intense epileptiform activity. To address the function of K<sub>Ca</sub>3.1 channels in glutamatergic neurons, we specifically overexpressed KCNN4 in these cells using a viral vector. Although overexpression did not abolish LRD generation, its duration and magnitude were significantly reduced, mirroring the effects of NS-309. These results demonstrate that the contribution of K<sub>Ca</sub>3.1 channels to epileptiform activity depends on its temporal pattern, with minimal influence on short LRDs but greater effects on robust glutamatergic activity at SLE onset. Thus, K<sub>Ca</sub>3.1 upregulation provides feedback mechanisms for the premature termination of epileptiform discharges, suggesting K<sub>Ca</sub>3.1 channels as potential therapeutic targets.</p>

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Calcium-Activated Potassium Channel KCa3.1 Shape Epileptiform Discharges in the Rodent Entorhinal Cortex

  • 期刊论文

  • 发表日期：

    2025年12月11日

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  • Elena B. Soboleva,
  • Dmitry V. Amakhin,
  • Denis S. Sinyak,
  • Evgeny S. Nikitin,
  • Anastasia A. Borodinova,
  • Victor N. Ierusalimsky,
  • Pavel M. Balaban,
  • Aleksey V. Zaitsev

摘要

The mechanisms underlying the generation and termination of epileptic discharges remain incompletely understood. This study investigates the role of KCa3.1 (KCNN4) channels in modulating epileptiform activity in the deep layers of the entorhinal cortex using two in vitro models: short-lasting late recurrent discharges (LRDs) and prolonged tonic–clonic seizure-like events (SLEs). Whole-cell patch-clamp recordings in rodent brain slices revealed that blocking KCa3.1 channels with TRAM-34 increased neuronal excitability and firing frequency, enabling sustained firing at higher depolarizing currents. In the LRD model, TRAM-34 had no effect on the frequency or duration of spontaneously generated LRDs, likely due to the low intrinsic expression of KCa3.1 channels in the entorhinal cortex. However, NS-309, a positive modulator of KCa3.1 and SK channels, reduced LRD duration, while TRAM-34 prolonged LRDs induced by extracellular stimulation. In the SLE model, TRAM-34 increased SLE frequency and enhanced glutamatergic activity at SLE onset, indicating a more pronounced role of KCa3.1 channels during intense epileptiform activity. To address the function of KCa3.1 channels in glutamatergic neurons, we specifically overexpressed KCNN4 in these cells using a viral vector. Although overexpression did not abolish LRD generation, its duration and magnitude were significantly reduced, mirroring the effects of NS-309. These results demonstrate that the contribution of KCa3.1 channels to epileptiform activity depends on its temporal pattern, with minimal influence on short LRDs but greater effects on robust glutamatergic activity at SLE onset. Thus, KCa3.1 upregulation provides feedback mechanisms for the premature termination of epileptiform discharges, suggesting KCa3.1 channels as potential therapeutic targets.