The Developing Epileptic Brain

Field: Neuroscience (Life Sciences)

Seizures arise commonly in infants and young children during acute febrile illnesses or following central nervous system (CNS) injury, but only a small percentage of children who experience early-life seizures develop epilepsy later in life. The reasons for these two phases of vulnerability are now becoming clear through the analysis of normal and abnormal brain development. We now know that many factors contribute to the heightened sensitivity of the immature brain to seizure activity, including a lag in the maturation of neuronal chloride gradients that creates a functional imbalance between excitatory and inhibitory synaptic neurotransmission in the brain. This stage is only transient, but it may be prolonged or even reemerge later in development due to the effects of genetic errors or acquired insults. A further challenge is to understand how the early-life seizures themselves alter the course of normal development to produce long-lasting changes in the excitability of neural networks, thus increasing the probability that epilepsy will develop in later life. Taken together, the serial layering of modifiers specific to each individual—genetic risk, maturation programs, early pathology, prolonged seizures, and finally the treatment regimen itself—illustrates the complexity of unraveling human epileptogenesis. This multifactorial etiology emphasizes the need to combine new research tools in developmental biology with clinical data to enhance our understanding and treatment of developmental brain disorders that are accompanied by an epileptic phenotype. The purpose of this year's Merritt Putnam Symposium is to help bridge the gap between bench and bassinet by increasing the clinician's awareness of the most recent technological and scientific advances in the early detection of biological lesions and their contribution to epileptogenesis in the immature brain. Ellen Grant describes new brain imaging techniques that allow clinicians to detect small focal lesions and congenital malformations associated with epilepsy with greater accuracy. She discusses the use of phased array technology and manual segmentation to compare the growth trajectories of specific cortical and subcortical nuclei of children with developmental disorders with those of normal age-matched controls. Dr. Grant explains that more subtle developmental differences can be identified through the use of diffusion tensor imaging and diffusion spectroscopic imaging, two techniques that are capable of precisely detecting defects in specific neuronal circuits underlying the functional pathology of epilepsy. Arnold Kriegstein, using evidence from time-lapse video recordings of organotypic slice cultures, outlines the generation and migration patterns of excitatory pyramidal neurons during the late stages of neurogenesis. He discusses the role of gamma-aminobutyric acid (GABA) and other epigenetic signals in the regulation of cell division, determination of cell fate, and the coordination of migratory movements within neuronal and interneuronal cell populations of the developing neocortex. Dr. Kriegstein points out that disruption of the distinct phases of neuronal migration can account for certain developmental disorders that are associated with epilepsy, thus underscoring the importance of studying the migratory strategies of cortical neurons. Pat Levitt extends the importance of understanding cell migration by focusing on the genesis of GABAergic interneurons and the molecular cues that guide their migration and intercalation into specific layers of the cortex. Using the uPAR knockout mouse as a highly instructive model of disrupted interneuron development, he presents evidence showing that a 50% reduction in the number of cortical interneurons produces long-lasting neurological and behavioral consequences. Dr. Levitt compares the behavioral commonalities seen between the uPAR mouse model and humans with epilepsy, schizophrenia, and autism, and concludes by suggesting that a developmental disruption of interneuron development may be a core component of each of these disorders. Amy Brooks-Kayal reviews our current understanding of GABAergic and glutaminergic receptor physiology and the maturational changes in the subunits of these receptors and related ion transporters that render the immature brain more susceptible to seizures. The developmental profile of these molecular rearrangements is a key element underlying differences in the sensitivity of the brain to the most frequently prescribed anticonvulsant medications. She then presents experimental evidence suggesting that early-life status epilepticus profoundly alters the molecular structure and function of these receptors in limbic circuitry, resulting in increased hippocampal excitability and a lowering of the seizure threshold in adulthood. These injury-induced changes superimposed upon an active program of neurodevelopment illustrate the complexity we face in deciphering the critical elements of epileptogenesis. Normal developmental changes create conditions that heighten the susceptibility of the immature brain to seizure activity that, in turn, sets the stage for the future development of epilepsy in vulnerable individuals. Darrell Lewis presents a thoughtful analysis of the major factors that predispose children to prolonged febrile seizures and increase their susceptibility to neuronal injury leading to mesial temporal sclerosis (MTS). He reviews the clinical and experimental evidence surrounding the role of three of these factors, hippocampal dysgenesis, prior febrile seizures, and genetic predisposition in the genesis of MTS. His conclusions, together with the forthcoming results from multicenter clinical studies, should help orient new experimental designs in the basic science laboratory that can focus the debate over the “two-hit hypothesis” currently being evaluated regarding the origin of epilepsy in MTS. Donna Ferriero defines the current strategies for neuroprotection in the developing brain—the use of targeted pharmacotherapies, preconditioning paradigms, and the enhancement of endogenous repair processes to minimize or prevent neuronal injury following hypoxic-ischemic insult. She discusses the sequence of key molecular events that follow brain injury, including the upregulation of target survival genes and their role in repair processes. Dr. Ferriero presents recent intriguing evidence suggesting that erythropoietin may have therapeutic potential in the treatment of ischemic stroke, and similar strategies may well be brought to bear upon epileptogenic lesions. It is hoped that this symposium will help clinicians gain a more clear understanding of the impact of early brain development on seizure susceptibility, the origin of epileptic lesions, and the role of developmental processes on the therapeutic response to treatment. Prolonged and repetitive seizures are associated with neuronal loss and a remodeling of vulnerable brain circuits, and this activity-dependent change further modifies the neural network. Neuroprotection is the ultimate therapeutic goal. The most recent scientific findings suggest that we need to explore the biology of the immature brain in order to correctly identify novel drugs that target the unique neurofunctional status of young patients to prevent epilepsy in later life. In addition, the early detection and treatment of children most vulnerable to the deleterious effects of early-life seizures remains a critical factor in determining the success of any therapeutic intervention.