By Dean A. Haycock

Special to BioWorld Today

Do you experience "partially synchronous oscillations within your thalamocortical circuits" night after night?

If so, don't be alarmed. Be grateful. Insomniacs envy you. It means the brain cells that connect the major relay center of your brain, the thalamus, to your cerebral cortex display the normal rhythmic activity that characterizes sleep.

If this synchronous firing of neurons becomes more than partial - if it becomes hypersynchronous - the situation changes from normal and enviable to medically serious. Hypersynchronous oscillations in neuronal firing in this brain circuit are a feature of absence epilepsy.

Formerly referred to as "petit mal," absence epilepsy manifests itself as motionless inattention, staring and blinking. The seizures are brief - 20 seconds or less in many cases - and often occur frequently during the day. A typical patient is a child whose seizures will regress in adulthood.

"It's nothing like a tonic-clonic grand mal seizure. And they don't lose muscle tone, either," said David McCormick, professor of neurobiology at the Yale University School of Medicine in New Haven, Conn.

As with the most forms of epilepsy, the cause or causes of absence epilepsy are unknown. A report in today's issue of Science, however, highlights an important feature of a system that appears to maintain normal patterns of nerve activity. Disturbances in this neuronal circuit could have significant implications for the study of absence epilepsy.

In the paper, "Reciprocal Inhibitory Connections and Network Synchrony in the Mammalian Thalamus," co-author John Huguenard, associate professor of neurology at the Stanford University Medical Center in Palo Alto, Calif., and his colleagues provide evidence that the brain relies on inhibitory connections within a part of the thalamus called the reticular thalamic nucleus (RTN) to keep things under control.

The authors believe absence epilepsy can be traced to a flaw in the neural mechanism that controls the normal sleep rhythm. According to this hypothesis, disruption of this mechanism results in neurons firing en masse in hypersynchrony. If this assumption is true, the important question naturally becomes: What stops the normal, partially synchronous nerve activity from spreading to many neurons to create the pathological state that results in seizures?

Experiments designed to answer this question could not have been performed without a strain of transgenic mice developed in co-author Gregg Homanics' lab at the University of Pittsburgh School of Medicine. These mice lack one subunit of a receptor for the major inhibitory neurotransmitter in the brain, GABA.

Inhibition Different In RTN

There are multiple types of GABA receptors. The missing piece in the knockout mice is the _3 component of the GABAA receptor. Within the mouse thalamus, most of this variety of GABA receptors are found in the RTN. Without the _3 subunit, GABA receptors in the RTN can't work; their inhibitory effect is largely obliterated. Using standard electrophysiological techniques, the researchers demonstrated this in slices of thalamic tissue from the _3 knockout mice. GABAA-mediated inhibition was not abolished, however, in other neurons in the thalamus called relay cells.

"We think that the form of inhibition that occurs there (in the RTN) is different than occurs elsewhere in the brain," Huguenard told BioWorld Today. The RTN cells send output to other areas of the thalamus where they produce inhibitory responses that last 10 milliseconds or so. But the RTN neurons also target themselves with what are called recurrent collateral connections, he said. These inhibitory responses may last hundreds of milliseconds.

It is these recurrent collaterals that are believed to dampen hypersynchrony.

"Ultimately, we think this is important in preventing the synchrony, in preventing epilepsy," Huguenard said.

The researchers also measured the extent of group firing among neurons in the knockout RTN tissue. They found it to be "dramatically intensified." They conclude "the recurrent inhibitory connections within the reticular nucleus act as 'desynchronizers,'" which normally prevent large groups of neurons from firing in a hypersynchronous fashion.

McCormick agrees that the findings are important for understanding absence epilepsy.

"What is new in this most recent paper is the use of knockout mice to test it (the hypothesis) in a living animal although they really didn't record from the animal," McCormick said. "That would have been nice. They recorded in vitro. So it was a different way to test the hypothesis, which already had a fair amount of support."

Mechanism Of Action Elucidated

Besides demonstrating the value of transgenic approaches to studying the mechanisms that regulate neural circuits in the brain, these studies may elucidate the mechanism of action of a prescribed anti-epileptic drug, clonazepam. Previous experiments demonstrated this drug decreases synchronous firing in the thalamus. It now looks as if it may do it by boosting the inhibitory effect of GABA in the RTN.

"Our characterization of clonazepam's effect suggests that there may be ways you can specifically modulate receptors in different parts of the brain to produce therapeutic effects," Huguenard said. "Specifically, if we can enhance the GABA responses within the RTN, then that should prevent absence epilepsy. The reason we will be able to do so is because the receptors are made up of different peptides which determine the sensitivity to different pharmacological agents."

To study the more complex aspects of the synchrony generated by activity in the RTN, Huguenard and his co-workers now are deriving computer models that assemble artificial neural networks.

The research was funded by grants from the National Institutes of Health, the Pimley Research Fund and the University Anesthesiology and Critical Care Medicine Foundation in Pittsburgh. n

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