(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine, in collaboration with
scientists at the City University of New York, have identified a
striking dysregulation in neuronal receptor activity in the postmortem
brain tissue from patients with schizophrenia. By stimulating receptors
in the prefrontal cortex, the research team tracked heightened levels
of erbB4 receptor activity, as well as decreased NMDA receptor activity
in the tissue from patients with schizophrenia. Additionally, they
were able to identify a relationship between these two receptor
groups, suggesting a mechanism for decreased NMDA receptor function
that has long been suspected in schizophrenia. The researchers report
their findings in this week's advanced online issue of Nature
Schizophrenia, a mental disorder afflicting approximately one percent
of the world population, is characterized by a variety of symptoms
such as: hallucinations, paranoia, disorganized behavior, and the
inability to experience pleasure. Previous studies of the brains
of patients with schizophrenia suggest altered function in the prefrontal
cortex, the brain's organizational center for cognitive function,
personality expression, and behavioral control. International, large-scale
genetic studies of patients with schizophrenia have pointed researchers
to a gene called neuregulin 1 (NRG1), which appears to
play a role in determining one's susceptibility to the disease.
Chang-Gyu Hahn, MD, PhD, Assistant Professor of
Psychiatry, Steven Arnold, MD, Associate Professor
of Psychiatry and Neurology, and Raquel Gur, MD, PhD,
Professor of Psychiatry, and colleagues at Penn, in collaboration
with Hoau-Yan Wang, PhD, at The City University of New York, took
an approach to use NRG1 protein to activate its neuronal receptor,
erbB4, to measure the molecular response in postmortem brain tissue.
The binding of NRG1 to erbB4 stimulates neuronal receptor activity
by adding phosphate molecules to the site of the receptor. The activation
of erbB4, in turn, kicks off a cascade of molecular events within
the neuron. When comparing the initial steps of neurochemical activity
in postmortem brain tissue of mentally healthy patients to those
with schizophrenia, the researchers discovered that NRG1-erbB4 activity
was significantly greater in the brains of patients with schizophrenia.
Hahn and colleagues also studied a second neuron receptor called
NMDA, which receives input from the neurotransmitter glutamate.
Previous studies at other labs have demonstrated the relationship
between erbB4 and NMDA receptor activity and have led researchers
to believe that enhanced activity of erbB4 receptors results in
a decrease in NMDA receptor activity.
Low levels of NMDA receptor activity are believed to contribute
to symptoms of schizophrenia. By stimulating NMDA receptors with
glutamate, and measuring the subsequent changes in phosphorylation
at the receptor, Penn scientists were able to track an impairment
in NMDA receptor activation in the postmortem brain tissue from
patients with schizophrenia.
"The fact that our studies of the brains of patients with schizophrenia
demonstrate both erbB4 receptor overactivity as well as NMDA underactivity
suggests the existence of a relationship between these two receptor
groups," explains Hahn. "Altered NRG1-erbB4 signaling
may contribute to NMDA receptor hypofunction in schizophrenia."
This finding is the first to display NMDA receptor hypofunction
in the brains of patients with schizophrenia.
ErbB4 and NMDA receptors are located at the post-synaptic junction,
or the chemical receiving end of the neuron. Both, erbB4 and NMDA
receptors, are bound to scaffolding proteins called post-synaptic
density (PSD), which can bridge receptor groups together and enhance
"PSD proteins can act like a raft in the ocean," explains
Hahn. "Just as holding onto a raft increases one's chance of
survival, by binding onto PSD proteins, NMDA and erbB4 receptors
can enhance their activity.”
Hahn hypothesizes that schizophrenia may be, in part, caused by
the convergence of multiple factors (both genetic and epigenetic)
at the PSD, which, in turn, alters the interaction of the molecules
in the cellular environment, resulting in the symptoms of schizophrenia.
In a continued attempt to understand the differences between the
brains of mentally healthy patients and those with schizophrenia,
future studies by the research team at Penn will focus on identifying
differences in interactive dynamics of proteins in the PSD.
The postmortem brain stimulation method, established in this study,
breaks out of the boundaries of previous research using postmortem
brain tissue. Postmortem studies have historically focused on snapshot
analyses of the brain at the time of death. This new method allows
investigation of functional responses of brain tissue to stimulation.
"Our hope is that this study will shift our postmortem methodologies
from limited comparative studies to a more experimental approach,”
explains Arnold. “This will allow us to tease apart the molecular
complexities that contribute to mental illnesses such as schizophrenia.”
Study co-authors are Dan-Sung Cho, Konrad Talbot, Wade H. Berrettini,
Joshua Kamins, Karin E. Borgmann-Winter, and Steven J. Siegel, all
from Penn, as well as Kalindi Bakshi, from The City University of
New York Medical School and Robert J. Gallop, from West Chester
University. This research was funded in part by the National Institutes
of Health and the Stanley Research Foundation.
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