Molecular Switch Boosts Brain Activity
Associated with Schizophrenia
Mouse Study May Yield Insight, New System for Drug Testing
People with schizophrenia have an alteration in a pattern of
brain electrical activity associated with learning and memory.
Now, researchers from the National Institutes of Health and Swedenís
Karolinska Institute have identified in mouse brain tissue a molecular
switch that, when thrown, increases the strength of this electrical
pattern. The researchers found that adding the brain chemical Neuregulin-1
to the brain tissue boosted the electrical signals that the tissue
"This finding may yield new insights into a form of altered
brain activity occurring in schizophrenia," said Duane Alexander,
M.D., director of NIHís Eunice Kennedy Shriver National
Institute of Child Health and Human Development (NICHD). "It
may also lead to new methods for screening drugs with potential
as schizophrenia treatments."
The findings appear online in the journal Cerebral Cortex.
The research was conducted by Andre Fisahn, Ph.D, of the Karolinska
Institute, in collaboration with Andres Buonanno, Ph.D, and his
colleagues in NICHDís section on Molecular Neurobiology. Dr. Buonanno
was the studyís senior author.
Schizophrenia affects about 1.1 percent of the U.S. population.
Symptoms include delusions, hallucinations, disordered thinking
and social withdrawal.
As nerve impulses travel through the brain, they emit weak electrical
signals that can be measured through sensors attached to the scalp.
The different parts of the brain emit different kinds of electrical
signals. These signals vary with the kinds of mental activity taking
place within the brain.
Dr. Buonanno and his colleagues studied electrical patterns known
as gamma oscillations. Ordinarily, gamma oscillations occur when
people are involved with learning and memory tasks, Dr. Buonanno
said. In people with schizophrenia, however, the strength of the
gamma oscillations is reduced.
"With schizophrenia, the gamma oscillations are fainter," Dr.
Buonanno said. "Itís analogous to tuning in the weak signal
of a distant station on your car radio, as opposed to picking up
the strong signal of a station thatís nearby."
Dr. Buonanno and his colleagues studied brain sections from the
hippocampus, a brain region involved in learning and memory. The
hippocampus also is a major source of gamma oscillations.
The researchers first chemically stimulated the brain sections,
in effect jump starting them so that they began generating gamma
oscillations. After the researchers exposed the sections to Neuregulin-1,
the strength of the gamma oscillations increased dramatically.
Like a key fits into a lock, Neuregulin-1 fits into a special
site, or receptor, on the surface of brain cells. Specifically,
Neuregulin-1 binds to the receptor known as ERB4.
Further tests confirmed the role of Neuregulin-1 in boosting gamma
oscillations. The researchers soaked the hippocampus sections in
a drug that blocks ERB4. When the researchers added Neuregulin-1,
the hippocampus sections did not show an increase in gamma oscillations.
Similarly, the researchers then added Neuregulin-1 to hippocampus
sections of mice that were genetically incapable of producing the
ERB4 receptor. Once again the animalsí brains failed to show any
increase in gamma oscillations.
The researchers chose to study Neuregulin-1 and ERB4 because earlier
studies had shown that people with schizophrenia often have alterations
in the genes that contain the information needed to make these substances.
"For the first time, we were able to show that Neuregulin-1,
which has been genetically implicated in schizophrenia, affects
a brain activity that appears to be altered in schizophrenia," Dr.
In addition, the researchers found that ERB4 receptors were abundant
on a particular type of neuron (a specialized cell involved in
the transmission of information). Known technically as parvalbumin
expressing neurons, these neurons slow the transmission of electrical
signals through the brain.
Studies performed at autopsy have found that people with schizophrenia
have fewer parvalbumin expressing neurons than do people who do
not have schizophrenia. In their study, Dr. Buonanno and his colleagues
reported that the mice which were genetically incapable of producing
the ERB4 receptor also have fewer parvalbumin expressing neurons
than do genetically normal mice.
"Our study has uncovered an interesting lead," Dr. Buonanno
said. "Future studies of brain regions rich in ERB4 receptors
may yield important information on the nature of schizophrenia."
Dr. Buonanno added that studies of how various drugs affect the
ERB4 receptor and parvalbumin expressing neurons may lead to novel
drug treatments for schizophrenia.
Other authors of the study were Jorg Neddens and Leqin Yan, also
of the NICHD Section on Molecular Neurobiology.
Information on schizophrenia is available from NIHís National
Institute of Mental Health at http://www.nimh.nih.gov/health/publications/schizophrenia/summary.shtml.
The NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation. For more information, visit
the Instituteís Web site at http://www.nichd.nih.gov/.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.