A mathematical model of neuroimmune interactions in epileptogenesis for discovering treatment strategies
Danylo Batulin,
Fereshteh Lagzi,
Annamaria Vezzani,
Peter Jedlicka,
Jochen Triesch
Affiliations
Danylo Batulin
Frankfurt Institute for Advanced Studies, Frankfurt 60438, Germany; Faculty of Computer Science and Mathematics, Goethe University, Frankfurt 60486, Germany; CePTER – Center for Personalized Translational Epilepsy Research, Frankfurt, Germany; Corresponding author
Fereshteh Lagzi
Frankfurt Institute for Advanced Studies, Frankfurt 60438, Germany; CePTER – Center for Personalized Translational Epilepsy Research, Frankfurt, Germany; Center for Computational Neuroscience and Swartz Center for Theoretical Neuroscience, University of Washington, Seattle 98195, USA; Department of Physiology and Biophysics, University of Washington, Seattle 98195, USA
Annamaria Vezzani
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano 20156, Italy
Peter Jedlicka
Frankfurt Institute for Advanced Studies, Frankfurt 60438, Germany; CePTER – Center for Personalized Translational Epilepsy Research, Frankfurt, Germany; ICAR3R - Interdisciplinary Centre for 3Rs in Animal Research, Faculty of Medicine, Justus-Liebig-University, Giessen 35390, Germany; Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Frankfurt 60528, Germany; Corresponding author
Jochen Triesch
Frankfurt Institute for Advanced Studies, Frankfurt 60438, Germany; Faculty of Computer Science and Mathematics, Goethe University, Frankfurt 60486, Germany; CePTER – Center for Personalized Translational Epilepsy Research, Frankfurt, Germany; Faculty of Physics, Goethe University, Frankfurt 60438, Germany; Corresponding author
Summary: The development of epilepsy (epileptogenesis) involves a complex interplay of neuronal and immune processes. Here, we present a first-of-its-kind mathematical model to better understand the relationships among these processes. Our model describes the interaction between neuroinflammation, blood-brain barrier disruption, neuronal loss, circuit remodeling, and seizures. Formulated as a system of nonlinear differential equations, the model reproduces the available data from three animal models. The model successfully describes characteristic features of epileptogenesis such as its paradoxically long timescales (up to decades) despite short and transient injuries or the existence of qualitatively different outcomes for varying injury intensity. In line with the concept of degeneracy, our simulations reveal multiple routes toward epilepsy with neuronal loss as a sufficient but non-necessary component. Finally, we show that our model allows for in silico predictions of therapeutic strategies, revealing injury-specific therapeutic targets and optimal time windows for intervention.
