Ion Channels and Epilepsy: From Molecule to Mouse to Medication

by Brenda Patoine

May, 2009

/uploadedImages/News_and_Publications/Special_Publications/Articles/1_jessell_thomas.jpg William A. Catterall, Ph.D.
Professor and Chair of Pharmacology
University of Washington


Q: Your research has focused on a form of epilepsy that is caused by a defect in ion channels, but epilepsy is but one of many so-called ion channelopathies. What are the common features of these conditions?

A: Ion channelopathies are diseases that are caused by mutations in the genes for certain ion channels. These mutations, while not severe enough to cause death before birth, change the function of the ion channel just enough to cause a disease state.

Ion channels, of which there are four main types (potassium, sodium, calcium and chloride), are the key signaling molecules that generate and regulate electrical signals in tissue. Defects in ion channels therefore interfere with their ability to properly regulate tissue function, and disease results. Since these channels are widely distributed in every tissue of the body, diseases of ion channels are also widespread; they may affect the skeletal muscles, kidneys, heart, and many other organs in addition to the nervous system.

The first ion channelopathies to be discovered were mutations of sodium channels that cause periodic paralysis of skeletal muscles; these were first reported in 1991-1992. In the case of epilepsy, a series of papers from 1998 to 2001 implicated mutations in different subunits of sodium channels as the root cause of two types of childhood epilepsy: a relatively mild form called Generalized Epilepsy with Febrile Seizures Plus and a devastating form of childhood epilepsy called Severe Myoclonic Epilepsy of Infancy (SMEI).

We now know that mutations in one type of sodium channel cause epilepsy, while mutations in another type cause periodic paralysis and yet others cause cardiac arrhythmias. That’s because different genes encode sodium channels in different tissues. There is a gene that encodes the skeletal muscle sodium channel; there is a different gene that encodes the primary cardiac sodium channel, and there are four different genes that encode sodium channels in the brain. So the same sorts of genetic defects can cause quite different diseases depending on which sodium channels and which tissues are affected.

Q: What spurred your interest in studying channelopathies?

A: I started working on ion channels at the beginning of my research career, when I was a post-doctoral fellow in the early 1970s. At that time, people were interested in studying the electrical signals in the brain and other cells, which are very important for regulating cell function. In the brain, electrical signals are how nerve cells talk to each other and how they send commands out to the periphery, to tell muscles to contract, for example. Sensory receptors in the peripheral parts of the body, including the eyes, ears, skin, etc., also send information back to the brain in the form of electrical signals. It’s been known for more than 100 years that ion channels make those electrical signals.

What wasn’t known, when I began working in the field, was the identity of the molecules that generate electrical signals. In the first part of my career, I worked on discovering the ion channel molecules, and we reported on those studies in a series of papers published in the 1980s. That was an important step toward understanding one aspect of how the brain works at the molecular level, because we were able to identify the molecules that generate electrical signals and study them in great detail by cloning their genes and experimenting with them. That was also the precursor to understanding ion channelopathies, because you can’t discover that an ion channelopathy is due to a sodium channel mutation until you know the structure of the sodium channel gene.

My work on ion channelopathies is really much more recent, having started in the last five years. We were first attracted to this question of inherited epilepsy because we were interested in making a genetic model of epilepsy in the mouse. We were intrigued by studies from human geneticists that suggested SMEI is caused by loss-of-function mutations in sodium channels—that is, by mutations that prevent the sodium channels from working.

This finding was a paradox, because sodium channels are responsible for driving the electrical signals in the brain and we know that epilepsy results from too much electrical signaling in the brain. Yet here was a form of epilepsy caused by a mutation that prevents sodium channels from working. We wondered why these mutations cause epilepsy, and we decided that inserting them into the mouse genome was a good way to figure it out. If the mouse developed epilepsy that was similar to human SMEI, it would be possible to study this disease in ways that are impossible in humans. We now have this mouse model of epilepsy and we have built an active research program around it.

Q: What have you learned by studying the SMEI mouse model?

A: The first interesting result from our work with the SMEI mouse model was the discovery that the particular gene that is mutated (called SCN1A) encodes sodium channels. These channels that are critical for the electrical excitability of inhibitory neurons in the hippocampus, an important region controlling excitability of the brain. Inhibitory neurons are one of two broad classes of neurons in the brain—the other is excitatory neurons, which “excite” or activate other cells. Inhibitory neurons release the neurotransmitter GABA onto nearby excitatory neurons, which quiets them down. There is always a dynamic balance between excitation and inhibition in the brains normal functioning.

One can think of this as the yin and yang of electrical signaling in the brain, where you have excitatory neurons activating circuits and signaling muscles to contract, for example, along with inhibitory neurons telling the excitatory neurons to slow down. You need to have a balance. In a sense, the inhibitory neurons are the traffic cops of electrical signaling in the brain. If they cannot make electrical signals and cannot tell the excitatory neurons to slow down, the excitatory neurons just have a party. The result is an epileptic seizure, which is essentially uncontrolled, synchronized excitatory transmission in the brain. The mutations we discovered in the SCN1A gene disrupt the delicate balance of electrical signaling in the brain by impairing the inhibitory side of the yin and yang.

Q: If a failure of inhibitory signaling causes seizures in SMEI, what might account for the other symptoms of this disease?

A: Other aspects of this disease may be explained in the same way. Like other epilepsies, SMEI has a number of comorbidities; that is, other disease symptoms that are separate from the seizures. In SMEI for example, children are ataxic: they have walking difficulties and abnormal gait, even when they’re not having a seizure. By far the most troubling comorbidity in these children is psychomotor delay: between ages one through four, their brain development and function either plateaus or regresses. They never really recover from that, proceeding through their teenage years with low IQ and poor motor skills and almost always requiring a caregiver for the rest of their lives. They have a number of other minor comorbidities as well, including sleep disorders and sensitivity to light.

Our thinking is that all of the comorbidities seen in SMEI are really due to the same root cause: the failure of inhibitory neurons to fire electrical signals in a normal manner. We’ve been studying this hypothesis in ataxia, which we thought might be explained by a malfunction in inhibitory neurons in the cerebellum, which controls movement. This turned out to be the case. In our mouse model, Purkinje neurons, an important set of inhibitory neurons in the cerebellum that coordinate movement, fail to fire normally. We think this is why we see ataxia in our mouse model and in children with SMEI.

Knowing that, we can imagine how other comorbidities might result from this same mechanism. For example, the cognitive impairment that we observe in our mice may be due to the failure of inhibitory firing in the part of the brain used for thinking about complex things, the cerebral cortex. We have not shown that specific result yet; it is still a hypothesis based on the results that we have shown in the cerebellum. We are also looking at other comorbidities to determine if they too are a result of a failure of inhibitory firing. It’s an active area of research for us, and I would guess that we will have a clearer view in a year or two.

Q: SMEI is a fairly rare form of epilepsy. How might better understanding of its pathogenesis lead to progress in more common epileptic syndromes?

A: SMEI is very rare, fortunately, because it is so devastating. The estimates of frequency of this kind of epilepsy have been increasing as diagnosis of it has become more widespread, and the current estimate worldwide is one in 20,000 births. I think it is significant because of its severity rather than how many people it affects.

On the other hand, it is fairly common for a child to have a seizure in the context of a fever or a disease, but it seldom develops fully into epilepsy. It is becoming increasingly understood that SMEI is responsible for many cases in which a child has a febrile seizure and then goes on to develop a complicated epilepsy syndrome.

Even though SMEI is rare and unique in many respects, there are two areas where we think this work may have an interesting and important impact on epilepsy research more generally. First, this sets a precedent for making mouse models of epilepsy by showing that you really can gain new insight into the basis of the disease using a mouse genetic model. We’ve made a genetic change in the mouse that is exactly what happens in humans and we think our mouse epilepsy looks just like the corresponding epilepsy syndrome in humans. We think this is a step forward into how to fashion experimental studies on the fundamental basis of epilepsy. I hope it will stimulate other scientists to make genetic mouse models to better explain the pathophysiology of other types of epilepsy.

I am also hopeful that the basic mechanisms that we will discover of how the brain becomes epileptic in SMEI may have commonalities with epilepsy in general. I suspect that there are a limited number of ways that the brain can lose control of its excitability; evolution has presumably made it very difficult for that to occur. If we can find the exact mechanisms that cause the brain to lose control of its electrical signaling in this model of epilepsy, it is possible that these mechanisms may have some generality for other, more common forms of epilepsy that are difficult to study.

Q: How is this understanding now being applied to therapeutic development?

A: Our hope certainly is to provide some therapeutic benefit for children with SMEI. One reason this particular childhood epilepsy is so devastating is because it is not well controlled by the existing panel of anti-epileptic drugs. In fact, some drugs that are prescribed frequently for other forms of epilepsy can actually make SMEI worse. There are sad stories of children being incorrectly diagnosed and treated with the wrong drugs, resulting in a worsening of their syndromes.

We think another opportunity for our mouse model is to explore some novel therapeutic approaches that are difficult to try in children, due to the very appropriate safeguards concerning testing new therapies in children and the small number of affected children who are available for clinical studies. In mice, we have much more latitude in the kinds of treatments we can try.

We have a program that is just ramping up to do what might be called “clinical trials” on mice. First, we want to see if we can find combinations of known drugs that will be efficacious in the mouse model and determine if it’s reasonable to try them in humans. We will investigate drugs that are already in the clinic or are in early development by drug companies but haven’t yet been fully tested clinically.

For example, there are drugs that can be used to enhance the actions of GABA, the inhibitory neurotransmitter. Some of these are used to treat epilepsy, and some are known in the research laboratory but are not yet used in treatment. We are trying to use novel combinations of drugs that act in different ways—synergistically we hope—to enhance neurotransmission by GABA neurons and therefore “tune up” the inhibitory electrical signals and restore the yin-yang balance of electrical signaling in the brain.

We have to find a treatment that will strengthen the inhibition without strengthening the excitation. We don’t know of a way to do that with drugs that act on sodium channels directly, but we think that we can do it with drugs that enhance the actions of the GABA. There are many so-called “GABA co-agonists,” drugs that enhance the strength of GABA signaling. The most famous is probably diazepam (Valium), and the one that is used most often in epilepsy is a relative of diazepam called clonazepam (Klonipin; Rivotril). There are other families of drugs that also enhance GABA neurotransmission in different ways but are not so widely used. We are currently treating mice with combinations of these drugs, and have found that the mice are more resistant to seizures and live longer. Based on those findings, we are optimistic.

Once we find the optimal drug combinations, we plan to treat the mice with them for a long time, as a child would be treated, to see if they continue to be effective. I think within the next year we will know whether the first set of ideas that we’re testing are going to bear fruit. It will be exciting for us if we can find novel treatments that are effective in our mouse model of SMEI and may hold promise for improving therapy of children with this devastating disease.