K⁺ channels as key modulators of in vitro high-frequency oscillations associated with interictal epileptiform...

The aim of this study was to explore how the dynamic relationship between interictal-like epileptiform discharges (IEDs) and high-frequency oscillations (HFOs; Ripples, Rs and Fast Ripples, FRs) changes following the inhibition of K⁺ currents or GABA_A receptor block in elementary hippocampal networks. Hippocampal slices were prepared from adult healthy rats (naïve, N) or rats that underwent a pentylenetetrazol-induced status epilepticus-like generalized seizure at postnatal day 20 (SE). Spontaneous IEDs were induced by Mg²⁺-free ACSF perfusion and were recorded from the CA3 pyramidal layer of the ventral and dorsal hippocampal slices. Rs and FRs coincided one-to-one with all IED events; Parameters describing their respective features and timing coincidence were measured before and during perfusion with the K⁺ channel blocker Tetraethylammonium (TEA, n = 36 slices) or the GABA_A antagonist Bicuculline methiodide (BMI, n = 36 slices). Both agents facilitated IEDs, TEA increasing their frequency and BMI their duration. However, TEA depressed Rs and FRs (and more so in ventral than in dorsal slices), whereas BMI had minimal HFO effects (in all slices). Pharmacological HFO modulation in SE slices was weaker compared to N slices. These findings show that the dynamic relationship between IEDs and HFOs depends on the mechanism of hyperexcitability, anatomic location and seizure history. They also raise the possibility that HFO drug-induced modulation may be correlated to cognitive or behavioral side effects of antiseizure medications.