The membrane origin of epileptic-related paroxysms: numerical experiments to model the transition from a pacemaker potential to paroxysmal depolarization shifts in the absence of synaptic inputs.

Paroxysmal depolarization shift (PDS) has been widely recognized as a characteristic feature of epileptic activity. The PDS is typically interpreted as a giant excitatory potential resulting from enhanced synaptic transmission, aligning with the prevailing understanding of epilepsy as a network mechanism that involves alterations in the balance of synaptic activity towards increased excitation. Several papers reported PDS recordings from single-cell snail neurons, and it has been hypothesized that PDS originates from abnormal pacemaker potentials. A physiologically inspired mathematical model was used to assess this hypothesis and examine the transition from a pacemaker potential to a PDS. By modifying several parameters in a first oscillation model, we demonstrated that it is possible to transition from fast, low-amplitude oscillations to slow, high-amplitude oscillations. Additionally, by smoothly adjusting specific biophysical parameters of the model, we could generate, long-lasting depolarizations resembling PDS in a bifurcation-like scenario. Notably, adding to this simplified model a spike-generating mechanism, former membrane biophysical changes evoked transitions from action potentials to doublets and PDS of increasing duration, as observed in single-cell recordings during dug-induced epileptic-like activity. Overall, our numerical experiments support the concept of pacemaker potential transitioning into the electrical characteristics of epileptic-like activity and suggest a potential scenario for this transition in the absence of synaptic inputs.