Most regions of the brain contain excitatory cells that feed information forward to produce a stimulatory response, and inhibitory cells that prevent overstimulation and keep things in check. The area of the brain studied by Huguenard and his team - the reticular thalamic nucleus (RTN) - is unique because it is composed entirely of inhibitory cells. These cells send out a flood of negative signals that decrease activity in other thalamic areas and impose a strong self-inhibition within the RTN. The self-inhibitory signals are received by specialized GABA receptors that contain the Beta 3 subunit.
For several years, researchers have suspected that the receptors were involved in absence epilepsy and Angelmans syndrome. The gene that encodes the Beta 3 subunit of the receptor is one of many genes absent in patients with Angelmans syndrome, and both groups of patients can experience similar seizures.
Using genetically deficient mice that lacked the receptors and displayed symptoms of Angelmans and absence epilepsy, the researchers documented how positive and negative signals in the thalamus adjusted to the loss of the receptors.
The mice lack one component in the circuitry that produces normal rhythms in the brain, said Molly Huntsman, PhD, postdoctoral fellow in Stanford's Department of Neurology and Neurological Sciences and lead author of the study.
The researchers found that the flow of signals was severely disrupted in mouse brain sections where the receptors were missing.
Huguenard describes the flow of signals between neurons in the thalamus as a type of juggling act. He likens the passage of information back and forth between groups of inhibitory and stimulatory cells, to a team of jugglers passing pins to each other.
In a healthy brain, only about 5 to 10 percent of neurons in the thalamus are involved in this juggling act at any point in time, although neuronal participation heightens as we fall asleep. Neurons from each team fire intermittently, says Huguenard. Like a team of jugglers packed tightly together with pins and elbows flailing, the self-inhibitory action of one RTN cell prevents a neighbor from performing the same motion at the same time.
But Huguenard's group believes that in the brain of people with absence epilepsy or Angelmans syndrome the self-inhibitory part of the circuit is lost and the juggling act becomes highly synchronized, so that all the pins are caught and released at the same time. This synchronization keeps almost all of the neurons busy, leaving none available for information flow.
"This juggling act prevents all sensory information from getting through," said Huguenard, explaining why children with this type of non-convulsive epilepsy have "absence attacks" lasting several seconds. These staring spells can occur several times a day. Although most children grow out of the disorder, it can disrupt learning and endanger the child if an attack occurs at a critical moment such as crossing the street. People with Angelmans syndrome suffer similar absence attacks in addition to other neurological symptoms.
Both disorders are rare. Approximately one percent of the population suffers from epilepsy of some kind, and only 2 to 10 percent of the people in this group have absence epilepsy. Angelmans syndrome, named for Harry Angelman, the physician who first described it in 1965, affects 1 in 20,000 people. The syndrome consists of an array of symptoms including a stiff, jerky gait, absent speech, excessive laughter and seizures.
The new findings earmark the Beta 3 GABA receptors for further research and a possible target for new drug therapy. "This defect is just one of many that may lead to absence," said Huguenard. "But it is the first time that a specific anatomical defect has caused a change in neuronal circuitry in the brain."
Researchers from the University of Pittsburgh School of Medicine and the Molecular Research Institute also contributed to the study. Funding was provided by the National Institutes of Health, the Pimley Research Fund and the University of Pittsburgh Anesthesiology and Critical Care Medicine Foundation.