History of Epilepsy Research
Epilepsy encompasses an array of brain activity disorders. Symptomatically, epilepsy can range from dramatic tonic-clonic seizures to subtle alterations in awareness that characterize absence seizures.
Over the last several decades, animal research has led to the development of increasingly effective treatments that have made life more manageable for people with epilepsy. Through the expanding field of epilepsy research using animals and their cells and tissues in vitro, multidisciplinary researchers are fine-tuning their understanding of the many genetic and environmental factors that contribute to epilepsy and are using this knowledge to develop improved treatments.
Some causes of epilepsy are clear — damage from trauma or other illnesses often underlie epilepsy — but about 70 percent of cases stem from unknown causes. In fact, the causes and manifestations of the disease are so varied that doctors now commonly refer to the affliction as “the epilepsies,” to reflect their diversity.
Seizures reflect abnormally synchronized patterns of activity in neural networks. These can remain localized to one brain region (e.g., partial seizures) or spread throughout the brain (generalized seizures). Initial understanding of the events that go awry during a seizure - and between seizures - came from electroencephalograms (EEG) of patients, which revealed distinctive signatures of abnormal brain activity. Early treatments for epilepsy were not ideal. Physicians recognized quickly that sedatives, such as bromides and barbiturates, suppressed seizures but were overly sedating. Surgery was crude and often took out too much healthy tissue. When doctors removed an epilepsy patient's medial temporal lobes bilaterally, it created one of the most studied cases of amnesia in medical history. The patient, who famously became known as HM, was cured, but lost the ability to create new memories. Today, thanks to the vital role of animal research, more than 12 antiepileptic drugs are available to control seizures with far fewer side effects. Common mechanisms include the blockade of sodium and calcium channels, currents which tend to increase neuronal excitation. Others facilitate inhibitory GABA neurotransmission, which serves to dampen the overall excitation in the brain. In addition to drugs, targeted surgeries to alleviate epilepsy use magnetic resonance imaging (MRI) and electrophysiological mapping techniques. Although the antiepileptic drugs and targeted surgeries have evolved tremendously over the past few decades, many patients don't benefit from them.
Animal research has already contributed heavily to the progress made in understanding causes and developing treatments for epilepsy. A major breakthrough came in the late 1970s using electrocorticography (ECG), with the observation that mice known for their wobbly gait, referred to as “tottering,” displayed spike-wave seizure activity remarkably similar to that seen in humans with epilepsy. Eventually, scientists traced the mouse epilepsy to a mutation in a specific gene, Cacna1a, which encodes a voltage-activated calcium channel, a protein that plays an important role in regulating neurons' cellular and electrical properties, including release of neurotransmitters. This provided the initial clue that even a single ion channel defect could produce epilepsy. Since then, more than 100 genes have been identified as contributing to epilepsy in mice and humans. Some of the mutations seen in mice arise spontaneously. Others have been genetically engineered into rodents, which has propelled scientists' ability to dissect the genetic influences of individual mutations and the ways they affect brain activity. While few forms of human epilepsy are caused by individual gene mutations, scientists are discovering that more subtle alterations in combinations of these genes can make a person more susceptible to epilepsy in the face of other influences (i.e., concussions, tumors, etc.).
Part of the difficulty in elucidating the root causes of epileptic seizures is that scientists have just begun to understand the ways that neurons and circuits signal to one another in normal, healthy brains. Researchers agree that most epileptic conditions likely arise from abnormalities in the two main functions of cortical networks: “firing” and “wiring.” “Firing” describes the intrinsic properties of the neuron's excitable membrane that allow it to rapidly signal with other cells, whereas problems with “wiring” of the network during development affect the way that cells communicate on a broader scale. Firing problems can often be traced to defects or mutations in ion channels, whereas wiring abnormalities are more likely to stem from mutations in proteins key to the transmission of signals at synapses, as well as the correct migration pattern of cells in the developing brain.
Other aspects of epilepsy that have more recently come to light from animal research are the importance of tonic inhibition (which keeps the brain in a resting state), the ability of the brain to reorganize its synapses, and the function of glial cells. Animal models allow critical opportunities to move these new findings toward treatments. For example, optogenetic technology now allows for cell-specific control of network firing to prevent seizures. Other researchers have repaired epileptic brain networks by transplanting interneuron precursor cells. Finally, mice have provided essential evidence underlying the relationship of epilepsy to conditions that come with it, such as memory impairment and even sudden death due to cardiac arrhythmias. As in many areas of neuroscience, future research in epilepsy is being guided by findings in animal models, which will provide clues to the human condition that cannot yet be discovered or advanced in the clinic.
References
Baraban SC, Southwell DG, Estrada RC, Jones DL, Sebe YJ, et al. Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice. Proceedings of the National Academy of Sciences of the United States of America. Sep 8; 106(36): 15472-15477 (2009).
Goldman AM, Glasscock E, Yoo J, Chen TT, Klassen TL, Noebels JL. Arrhythmia in Heart and Brain: KCNQ1 Mutations Link Epilepsy and Sudden Unexplained Death. Science Translational Medicine. Oct 14; 1(2): 2ra6 (2009).
Krook-Magnuson E, Armstrong C, Oijala M, Soltesz I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nature Communications. Jan 22; 4: 1376 (2013).
Noebels JL, Sidman RL. Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering. Science. June 22;204:1334-1336 (1979).
Palop JJ, Mucke L. Epilepsy and Cognitive Impairments in Alzheimer Disease. Archives of Neurology. April; 66(4): 435 (2009).
