Exploring the likelihood of the membrane pollution hypothesis with a physiologically plausible biophysical model.

Epilepsy affects more than 52 million people worldwide and has been known since ancient times. Despite this long history, available therapeutic methods--both pharmacological and non-pharmacological--fail to control seizures in over 10% of patients. At the same time, there exists a diversity of theories regarding the fundamental mechanisms underlying epilepsy. Understanding the biophysical basis of the simplest manifestation of epileptic activity--the paroxysmal depolarization shift (PDS)--could therefore be highly valuable. Prevailing ideas consider PDS as exaggerated synaptic excitatory potentials, but experimental evidence shows that PDS can be generated in isolated neurons devoid of synaptic input. Ulrich Altrup proposed an alternative view, suggesting that PDS represent aberrantly large pacemaker potentials rather than giant excitatory postsynaptic potentials. Theoretical work by Hernandez-Caceres and Brenes supported this concept, demonstrating a bifurcation-like transformation from physiological pacemaker potentials to PDS and finally to long-duration sustained depolarizations. According to Altrups membrane pollution hypothesis (MPH), epileptic activity emerges as a consequence of incorporating amphiphilic pollutants into neuronal membranes, which leads to an increase in membrane micro-viscosity. Using a biophysically sound model for pacemaker activity, we explored the possibility of eliciting PDS through increased membrane micro-viscosity. Provided results suggest that this is theoretically plausible. Further experimental and theoretical research is needed to refine details of the MPH and to develop new strategies for combating epilepsy.