Pathophysiological levels of extracellular calcium and potassium induce seizure-like discharges: identification of synaptic and nonsynaptic components.

Abstract

Although glutamatergic and GABAergic synapses are important in seizure generation, the contribution of nonsynaptic ionic and electrical mechanisms to synchronization of seizure-prone hippocampal neurons remains unclear. Here, we developed a physiologically relevant in vitro model to study these mechanisms by inducing prolonged seizure-like discharges (SLDs) in hippocampal slices from male rats through modest, sustained ionic manipulations. Specifically, we reduced extracellular calcium to 0.8-1.0 mM and elevated potassium to 6-12 mM, mimicking pathophysiological states observed in vivo during brain injury, hypocalcemia, or intense neuronal activity. These ionic shifts reliably generated SLDs in the dentate gyrus and CA1. The SLDs could last tens of seconds and exhibited an evolution in waveform, pattern, and complexity-common and important characteristics of seizures in vivo, including spontaneous recurrent seizures recorded from freely behaving rats with kainate-induced epilepsy. In CA1, the SLDs continued to occur after evoked synaptic responses were eliminated with glutamate- and GABA-receptor antagonists. The blocker-resistant SLDs typically had an altered frequency and duration with reduced temporal waveform complexity. Thus, nonsynaptic ionic and electrical mechanisms can sustain and synchronize SLDs that do not require glutamatergic and GABAergic transmission; however, these neurotransmitter systems contribute significantly to the frequency, duration, and temporal complexity of the discharges. This work demonstrates that seizure generation can occur independently of classical synaptic transmission, highlighting the relevance of nonsynaptic mechanisms in seizures arising under metabolic or injury-related conditions. However, synaptic transmission contributes to the temporal evolution and complexity of seizures-hallmarks of clinically observed seizure activity.NEW & NOTEWORTHY Modest, sustained reductions in [Ca²⁺]_ex and increases in [K⁺]_ex reliably induce seizure-like discharges (SLDs) in hippocampal slices, mimicking key features of spontaneous seizures in vivo. These SLDs consistently persist after synaptic blockade with glutamate- and GABA-receptor antagonists, but often with altered duration and frequency and reduced temporal complexity. Thus, nonsynaptic ionic and electrical mechanisms can synchronize hippocampal neurons during SLDs, whereas chemical synapses contribute to their frequency, duration, and waveform complexity.