Faulty receptors may
contribute to absence epilepsy, Angelmans syndrome
BY KRISTIN WEIDENBACH
Stanford scientists have
discovered that loss of a population of receptors in the
brain upsets the brain's normal rhythms and changes its
neuronal circuitry. The receptors are found in a region
of the brain that controls attention, sleep and possibly
memory consolidation, and help to balance the positive
and negative signals processed in this part of the brain.
A signal imbalance created by these malfunctioning
receptors may be one of the defects underlying
neurological disorders such as Angelmans syndrome and
absence epilepsy, according to John Huguenard, PhD,
associate professor of neurology and senior author of the
study published in the January 22 issue of Science.
Most regions of the brain
contain excitatory cells that feed information forward to
produce a stimulatory response, and inhibitory cells that
prevent over-stimulation and keep things in check. The
area of the brain that Huguenard and his team studied
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 spe- cialized 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 that patients with Angelmans syndrome
lack, 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 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. SR
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