The coordinated activity of neuronal circuits underlies the brain's ability to encode and store information and to carry out cognitive and sensorimotor tasks. However, aberrant changes to neural activity, such as the increased synchronization of neuronal firing, can result in seizures. Recurrent, spontaneous seizure activity is a primary characteristic of epilepsy, a chronic disorder that affects over 65 million people worldwide. Although anticonvulsant drugs have been available for many decades and show some efficacy in a subset of patients, finding a true 'cure' for the epilepsies will require deeper knowledge of the events and conditions that drive abnormal neuronal firing. In recent years, advances in our understanding of the mechanisms that regulate neuronal excitability and modulate circuit activity have begun to provide some insight. In this issue, we present a special focus on epilepsy that highlights recent research that has expanded our understanding of the pathogenic events leading to aberrant brain activity and the molecular- and circuit-level changes driving pathogenic alterations in neuronal excitability.

Over the past few decades, approaches aimed at identifying genetic mutations associated with epilepsy and/or seizure phenotypes have resulted in a veritable explosion of potential gene targets. In a Review on page 344, Jeff Noebels examines recent advances in the identification of new genes underlying the onset of epilepsy. Many of these genes seem to functionally converge on neuronal excitability and synaptic inhibition, suggesting that analysis of the functional network of genetic interactions, a lesson learned from approaches that have served the cancer fields well, may facilitate future diagnostic approaches and help prioritize potential therapeutic targets.

Although the relationship between many of these genes—such as those encoding ion channels and regulators of neuronal signaling and excitability—and the generation of seizures seems logical, the mechanism of action of many other epilepsy-associated genes is less clear. Even among the genes with seemingly obvious links to impaired excitation or inhibition balance, it is still not clear how the timing of seizure transitions are regulated; that is, why patients with these genetic mutations do not have constant seizures. In a Review article on page 367, Kevin Staley discusses recent work exploring the molecular mechanisms that may underline seizure timing and the modes by which brain activity becomes predisposed to periodic seizures.

Although we have made strides in understanding the molecular deficiencies contributing to neuronal dysfunction in epilepsy, further insight into how altered function at the circuit level leads to the generation of seizures is still needed. In particular, it is still unclear how increased synchrony in local microcircuits following an initial insult then propagates throughout the cortex and even to distal regions of the brain. On page 351 of this issue, Jeanne Paz and John Huguenard discuss recent evidence that has changed the way that we view the function of brain microcircuitry and the mechanisms by which dysfunction in different circuits may contribute to seizure generation and propagation. In addition, the authors propose the idea that these microcircuits may act as choke points that regulate the spread of seizures and, as such, could represent intriguing targets for therapeutic intervention.

Much of what we have learned about the mechanisms that initiate and drive seizures has come from studies performed in non-human animal models. Given that no one model fully recapitulates all aspects of human epilepsy, it is critically important to bear in mind the strengths and weakness of each. In a Perspective on page 339, Brian Grone and Scott Baraban not only describe how 'traditional' systems, mainly rodent models, have provided insight into mechanisms of epileptogenesis but also discuss the areas in which these organisms fail to adequately model the human disorder. The authors advocate for increased use of 'simpler' model organisms, such as zebrafish and Drosophila, which can be easily and rapidly manipulated, making them useful for the modeling of genetic epilepsies. In addition, given their small size and large number of offspring, these nontraditional epilepsy models may serve as the perfect platform for large volume analysis of in vivo manipulations, potential drugs and/or therapeutic approaches.

Animal models are not the only tools available for examining mechanisms of epilepsy. With the advent of techniques for generating induced pluripotent stem cells from patient tissue, a whole new avenue of investigation has become available. On page 360, Jack Parent and Stewart Anderson review recent advances in the use of stem cells both to model the cellular changes contributing to epileptogenesis and as a tool for high-throughput screening. The authors also discuss the use of directed stem cells for cell-replacement and circuit-modulation therapies.

Although cell replacement therapies may hold great promise for future intervention in patients, others have been looking to recent technological advances in on-demand circuit manipulation to design potential therapeutic strategies. The emerging repertoire of light- or ligand-induced probes that allow for rapid activation or silencing of selected neurons (and therefore circuits) may yet be put to use in the clinic. In a Perspective on page 331, Esther Krook-Magnuson and Ivan Soltesz examine recent work using DREADDs or closed-loop optogenetic probe–mediated systems to 'short-circuit' seizures in animal models. The authors look ahead to how these approaches might be implemented in epilepsy patients, outlining the challenges that will need to be overcome for this therapeutic strategy to become a clinical reality.

The work described in the Reviews and Perspectives presented in this special issue represents the most exciting and innovative research aimed at elucidating the genetic, cellular and circuit-level mechanisms underlying this disease. Our goal is not only to present a comprehensive view of the epilepsy field but also to highlight the approaches that will drive future avenues of investigation and the therapeutic interventions that may result from these advances.