Contact: Nick Miller

513-803-6035
Cincinnati Children's Hospital Medical Center

Intestinal protein may have role in ADHD, other neurological disorders

CINCINNATI A biochemical pathway long associated with diarrhea and
intestinal function may provide a new therapeutic target for treating
ADHD (Attention Deficit Hyperactivity Disorder) other neuropsychiatric
disorders, according to a team of scientists from China and the United
States reporting Aug. 11 in Science.

Scientists have for the last quarter century studied the intestinal
membrane receptor protein, guanylyl cyclase-C (GC-C) for its role in
diarrheal disease and other intestinal functions, according to
Mitchell Cohen, M.D., U.S. author on the study and director of
Gastroenterology, Hepatology and Nutrition at Cincinnati Children's
Hospital Medical Center. In fact, it had been thought that GC-C was
found primarily in the intestine.

In the current study, scientists in China who collaborated with Dr.
Cohen discovered that the receptor is also expressed in critical areas
of the brain. The senior author on the study is Dr. Minmin Luo, a
researcher at the National Institute of Biological Sciences and
Tsinghua University in Beijing.

Using a mouse model developed in Dr. Ralph Giannella's laboratory at
the University of Cincinnati, in which the GC-C receptor is deleted,
or knocked out, the researchers found the mice exhibit hyperactivity
and attention deficits. It is the first time that GC-C has been linked
to neuropsychiatric disorder, according to the researchers.

"We show that the neurons selectively express GC-C and that its
activation amplifies the excitatory responses mediated by other
receptors on dopamine neurons in the midbrain," said Dr. Luo. "Working
through a protein kinase called PKG, GC-C activity increases brain
dopamine levels and thus regulate mouse attention and activity level."

When the researchers treated the GC-C knockout mice with amphetamine-
based ADHD medication and a PKG activator, it reversed their
hyperactive, inattentive behavior.

"The results indicate important behavi{*filter*}and physiological functions
for the GC-C/PKG signaling pathway in the brain," said Dr. Luo. "The
data also suggest new therapeutic targets for neuropsychiatric
disorders related to malfunctions of midbrain dopamine receptors."

One of the most prevalent human behavi{*filter*}disorders, ADHD has been
linked to imbalances in the dopamine system. The researchers noted in
the study that its findings mice exhibiting reduced dopamine levels
and related behavi{*filter*}problems are consistent with the biochemical
characteristics of human ADHD.

"This could make the GC-C knockout mouse a good research model for
ADHD and other behavi{*filter*}disorders," said Dr. Cohen. "Efforts to
develop activators or inhibitors of the GC-C/PKG signaling pathway may
lead to novel treatments for other disorders, such schizophrenia,
Parkinson's disease and {*filter*}ion."

###
The first author on the study is Rong Gong, who is in the joint
graduate program of Peking Union Medical College and the National
Institute of Biological Sciences in Beijing. Other institutions
collaborating on the study include: the College of Life Sciences,
Beijing Normal University and the Wuhan Institute of Physics and
Mathematics at the China Academy of Sciences in Wuhan, China.

http://www.***.com/ #