| Sometimes
when you turn off a car engine it will continue to run for a while
on its own. The cylinders keep firing even though they shouldn’t.
This condition is called dieseling and indicates a problem with
the motor that needs to be fixed. Something similar happens in
the brain of a person with epilepsy.
Have you ever seen somebody stop doing something
and just shake, or stare into space? If you have, it can be pretty
scary. That person may be having a seizure.
Seizures are one symptom of epilepsy.
Epilepsy is characterized by frequent seizures. One important
fact to remember: there are many types of epilepsy that may affect
muscle control, mental focus, speech, even consciousness.
Epilepsy affects more than 2 million Americans.
The illness can start in infancy, childhood, teen years, maturity
or old age. But once it starts, it becomes a lasting condition
of the patient.
Epilepsy may arise from conditions in the
patient’s brain at birth. Or, it may be caused by an injury
such as head trauma, or what doctors call an insult, such as a
drug overdose, viral or bacterial infection, inflammation or fever.
One type of epilepsy called temporal lobe epilepsy does not necessarily
occur immediately. It may take years or even decades before the
symptoms of temporal lobe epilepsy appear.
Patients and physicians need new treatments
for epilepsy. Why? The current treatments are far less than perfect.
Drugs that reduce the occurrence of seizures can have severe side
effects even if they control the seizures. Epileptics whose seizures
are not effectively controlled by drug therapy will often have
brain surgery to remove large parts of the hippocampus
where the seizure is thought to begin. But taking out parts of
the brain always has a consequence: in this case it can result
in severe short-term memory loss and learning disabilities.
“These surgical options don’t
work well for many epileptics, and cause awful side effects even
if they do,” says Dr. Shelley Russek, who studies epilepsy
at the Boston University School of Medicine. She and her research
team are trying to understand the basic mechanisms of temporal
lobe epilepsy. That is the only foundation on which better future
treatments for epilepsy may be constructed.
Her work has led to a discovery: a
change in the molecular structure of a receptor (part of a nerve
in the brain) has been shown to cause a form of epilepsy.
This is the first time a change in such a molecular structure
has been conclusively shown to cause a disease. It is often true
that a tiny, minuscule change in your body can have enormous consequences.
Here is the story behind the Boston
University breakthrough.
The human brain includes almost 100 billion
nerve cells (www.epilepsy.com).
For those of you with a mathematical bent, that’s 10¹¹.
These nerve cells (officially called neurons)
send messages to each other using electrical impulses. How do
neurons send messages?
Neurons are separated by a space called a
synapse.
When a neuron wants to communicate with another neuron, it releases
chemicals known as neurotransmitters
that travel across the synapse to the next neuron . The neurotransmitters
stimulate the next neuron
to fire. All this happens pretty fast. Why do neurons need to
communicate? To start muscles, create memories, recall facts,
hold your breath, react to danger; in fact, anything the brain
controls requires electrical impulses traveling along neurons.
Not too much. Not too little.
The firing of a neuron is a delicate balance:
first, starting the release of neurotransmitters and then, when
necessary, stopping it. Vocabulary to know: when a neuron is releasing
neurotransmitters it is excited;
to stop it, the neuron must be inhibited.
In normal circumstances, this happens automatically in your brain.
If a neuron is not stopped (inhibited), it
will continue to fire like the dieseling auto engine and will
continue to send messages to other neurons, causing them to fire
too. In the normal brain, a neuron may fire 80 times per second,
but during an epileptic seizure, a neuron may fire up to 500 times
per second (www.epilepsy.com).
The current theory on the cause of an epileptic seizure is that
certain neurons are not inhibited, so they continue to fire, in
a cascade of over-excitation.
So, fully understanding inhibition –
stopping – of this firing is critical to understanding epilepsy.
“The pauses between excitation are just as important as
the excitation itself”
says Dr. Russek.
Here’s where it gets a little complicated,
but also very interesting: Inhibition is controlled by a specific
neurotransmitter called gamma-amino butyric acid (thankfully,
shortened to GABA).
GABA works by attaching to little structures
in the cells called receptors.
Once the GABA attaches to a receptor, a specific chemical reaction
takes place. In neurons, the important receptors are called GABA(A)
receptors: they are crucial to inhibition.
| 1. |
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When
a neuron fires, GABA binds to the GABA(A)
receptor in the neuron. |
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| 2. |
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The GABA(A)
receptor opens a hole in the neuron’s membrane. The
hole is specific for the negatively charged chloride ion
(Cl-). |
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| 3. |
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Cl- will
go into the neuron, and inhibit it. |
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However,
if the GABA(A) receptor is not
functioning properly, the neuron will remain in an excited,
firing state. |
Dr. Russek and her research colleagues study
the behavior of GABA(A)
receptors as a cause of Temporal
Lobe Epilepsy (TLE). Dr. Russek and her collaborator at the
Children’s Hospital of Philadelphia, Amy Brooks-Kayal, use
an animal model that simulates the initial injury, which is followed
by the development of chronic seizures or epilepsy in rats.
The researchers knew that there were many
subunits of GABA(A)
receptors and that there was a specific gene for turning each
subunit ON or OFF. They discovered that just before a seizure,
changes occurred in the levels of specific parts of two subunits.
Specifically, the mRNAs
of the α4 subunit gene receptor increased (turned ON) and
the mRNAs of the α1 subunit gene decreased (turned OFF).
(Scientists like to use Greek letters: in this case, the letter
α, pronounced alpha.) Somehow the subsequent change in the
molecular composition of the GABA(A)
receptors was resulting in a seizure.
To study this change in gene expression,
Dr. Russek and her collaborator Dr. Brooks-Kayal created a virus
that would use the genetic switches in the α4 subunit gene
to deliver the α1 gene product. This process is called viral
vector gene transfer. “The viral model is perfect
for this kind of work,” says Dr. Russek, “because
viruses are experts at getting into the cells and we can put them
exactly where they are needed.” The researchers injected
the virus into a part of the brain that is the site of most seizure
activity.
Two weeks after injection Dr. Russek and
her colleagues found that the injected virus increased the levels
of the α1 GABA(A)
receptor subunit in the rat brains. When rats were injected with
the virus before developing continued seizures, the rats
did not develop spontaneous epilepsy. “We demonstrated that
expression of GABA(A)
receptor subunits is important in inducing a seizure,” says
Dr. Russek.
These researchers also demonstrated that
the α1 subunit is important in maintaining inhibition in
the brain and may be one of the keys to determine if epilepsy
occurs after an injury. This is the first time a change in the
expression of one subunit of a multi-subunit receptor has been
associated with a disease like epilepsy.
These results are exciting, but the team
has not yet determined whether the virus acted to suppress the
seizures or whether it actually prevented the development of the
epileptic condition. This is an important distinction to determine
how the findings can best be translated into a treatment.
Dr. Russek and Dr. Brooks-Kayal would like
to see something done about the plight of people with epilepsy
in this country. One option is gene therapy.
A virus similar to the one used in rats could be injected into
the brain of an epileptic to suppress seizures. “Gene therapy,”
says Dr. Russek, “has a promise for being used in the near
future (10 years) by neurosurgeons as a treatment for epilepsy
and much work is going into making more stable viruses with less
toxicity.”
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