Epileptogenesis is a complex multifactorial pathologic process underlying “the development and extension of brain tissue capable of generating spontaneous seizures” (Pitkänen and Engel, 2014); therefore, this process is responsible for the onset, development, and progression of epilepsy. In the last decade, advancement in understanding the basic mechanisms of epileptogenesis, and their temporal evolution during disease development, determined some conceptual changes that bear relevance for designing therapeutic interventions. In this context, experimental studies have provided evidence for various brain molecular and cellular changes initiated by the (acquired or genetic) insult and progress beyond the first unprovoked seizures (Dudek and Staley, 2011; Pitkänen et al., 2015). Spontaneous seizure frequency and severity may also progressively increase over several weeks post-insult (Galanopoulou and Moshé, 2015; Gorter et al., 2001; Iori et al., 2016; Kadam et al., 2010; Pauletti et al., 2019; Qiao and Noebels, 1993). The evidence for progressive changes and increased seizures has broadened the therapeutic window of intervention to include both disease prevention (anti-epileptogenesis) and improvement of its clinical course (disease modification).

Another leap forward in our knowledge provided by investigations in animal models of both acquired and genetic epilepsies relates to the appreciation of the spatial and temporal dynamics of brain modifications during epileptogenesis. These dynamics led to the new notion that epileptogenesis is not a step-wise phenomenon but instead a continuum of cellular/structural, molecular, genetic/epigenetic, and functional modifications (Pitkänen et al., 2015). Notably, some cellular and structural alterations ignited by the inciting insult (e.g., status epilepticus, neurotrauma, gene mutation), such as neuronal cell loss, axonal plasticity/mossy fiber sprouting, and neurogenesis, appear to reach a plateau when chronic seizures are established but may continue for other components of epileptogenesis. For example, glial cell plasticity, blood–brain barrier dysfunction, transcriptomic changes, and epigenetic changes are dynamically influenced by seizure onset and recurrence, and reciprocally contribute to seizures, thus establishing a pathologic vicious cycle. Thus, therapeutic interventions against epileptogenesis should take into careful account the timing of target engagement during disease development. This certainly represents a challenge for future research in this field, since timing will drive the choice between a preventive or a disease-modifying intervention.

New knowledge of mechanisms contributing to epileptogenesis, as attained over the last decade, includes the refinement of causes and consequences of neuronal and network maladaptive plasticity, the contribution of non-neuronal cells such as glia, immune cells, and the microvasculature, and the very recently emerging role of the gut-microbiome axis (not addressed in this edition due to the infancy of the topic). A far more precise grasp of epileptogenic mechanisms is now possible, thanks to technological advances in multielectrode electrophysiological and optogenetic approaches, high-resolution microscopy, and single-cell transcriptomic and omic approaches, as well as the possibility of using cell- and target-specific conditional manipulations in animal models (e.g., chemical genetic approaches, gene therapy, gene editing).

Section 3 of this book includes up-to-date information on mechanisms of epileptogenesis as discovered in animal models and validated in human brain tissue from drug-resistant epilepsies.

In particular, the section begins with three chapters related to changes in neuronal cells and circuits with a special focus on dentate gyrus plasticity, including cell loss, circuit rearrangement (Chapter 23 by Scharfman; Chapter 24 by Sloviter), and neurogenesis (Chapter 25 by Cho and Hsieh), and their consequences for excitation/inhibition imbalance, seizure threshold, and comorbidities. Four subsequent chapters are devoted to non-neuronal cells, with a focus on astrocytes (Chapter 26 by Bedner et al.; Chapter 27 by Murugan and Boison; Chapter 28 by Yang et al.), pericytes and microglia (Chapter 29 by Marchi and Brewster), and microvasculature (Chapter 29 by Marchi and Brewster; Chapter 28 by Yang et al.), and how changes in their activation state, metabolism, and phenotype contribute to the hyperexcitability underlying seizures. The next chapters report key signaling pathways that offer new strategies for anti-epileptogenesis/disease modification in both early and advanced disease development (Chapter 30 by Dingledine et al.; Chapter 31 by Sri Harai et al.; Chapter 32 by Harward et al.; Chapter 33 by Mathy and Irani), some of which have already translated to the clinic and represent novel examples of precision medicine (e.g., neuroinflammation, mTOR, auto-antibody targeted therapies) (Hébert et al., 2022; Lai et al., 2020; Luo et al., 2022; Moloney et al., 2021; Specchio et al., 2022; Uy et al., 2021; Vezzani et al., 2019). The two final chapters describe the latest discoveries in transcription factors (Chapter 34 by Brennan and van Loo) and epigenetic alterations (Chapter 35 by Kobow and Khan) detected in human patients and experimental epilepsy models affecting the gene expression landscape during seizure development and progression. The potential for targeting these genome modulators as a new source of therapeutic intervention in epilepsy is discussed.

Future challenges for the elucidation of mechanisms driving epileptogenesis must face the complexity and heterogeneity of this process triggered by diverse precipitating events. So far, epileptogenesis has been mainly investigated in models of acquired brain injuries, such as neurotrauma, status epilepticus, central nervous system infections, and hypoxia/ischemia. Whether the mechanisms characterized in these conditions are relevant for epileptogenesis induced by congenital or genetic causes warrants validation in relevant models and human tissue. Accordingly, new and refined animal models are being developed using genetic or acquired manipulations in the attempt to reproduce epileptic phenotypes that mimic human conditions which will also help to discover mechanistic biomarkers of the disease and to test therapeutic interventions. The full extent to which acquired epileptogenic injuries share common pathologic mechanisms of disease onset and progression has yet to be elucidated, although there is supportive evidence for some commonalities (Klein et al., 2018; Pitkänen et al., 2015; Varvel et al., 2015). A mechanistic approach to the discovery of key pathogenic brain modifications causing seizure onset, recurrence, and progression remains instrumental for designing rationale therapeutic interventions.