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Developing effective therapies against epilepsy remains a challenge. Thecomplex and multifaceted nature of this disease still fuels controversies aboutits origin. In this perspective article, we argue that conflicting hypothesescan be reconciled by taking into account the degeneracy of the brain, whichmanifests in multiple routes leading to similar function or dysfunction. Weexemplify degeneracy at three different levels, ranging from the cellular tothe network and systems level. First, at the cellular level, we describe therelevance of ion channel degeneracy for epilepsy and discuss its interplay withdendritic morphology. Second, at the network level, we provide examples for thedegeneracy of synaptic and intrinsic neuronal properties that supports therobustness of neuronal networks but also leads to diverse responses toictogenic and epileptogenic perturbations. Third, at the system level, weprovide examples for degeneracy in the intricate interactions between theimmune and nervous system. Finally, we show that computational approachesincluding multiscale and so called population neural circuit models helpdisentangle the complex web of physiological and pathological adaptations. Suchmodels may contribute to identifying the best personalized multitargetstrategies for directing the system towards a physiological state.

Degeneracy in epilepsy: Multiple Routes to Hyperexcitable Brain Circuits and their Repair