Posts tagged mental illness

July 27, 2012 

(Medical Xpress) — Johns Hopkins scientists have discovered a “scaffolding” protein that holds together multiple elements in a complex system responsible for regulating pain, mental illnesses and other complex neurological problems.

Preso1 (green) and mGluR5 (red) appear in the same location inside a neuron.

The finding, published in the May 6 issue of Nature Neuroscience, could give researchers a new target for drugs to treat these often-intractable conditions.

The discovery, detailed in a study led by neuroscience professor Paul Worley, M.D., of the Johns Hopkins University School of Medicine, focuses on a family of proteins called group 1 metabotropic glutamate receptors (mGluRs) that lie on the surfaces of nerve cells. When these receptors lock in glutamate, a chemical that neurons use to communicate, it encourages neurons to fire.

Without a way to turn off these receptors, neurons would remain active indefinitely, keeping pain and other responses going long after they’re useful. Previous research suggested that these mGluRs need to bind to another protein called Homer to shut down, and that this binding is stronger after other molecules called protein kinases modify the receptors. However, Worley explains, thus far it’s been unclear exactly how all these different players come together.

Seeking the mechanism behind this phenomenon, Worley and his colleagues started with a series of experiments to see what other proteins the mGluRs and Homer were binding with in rat brains. Their search turned up a third protein called Preso1, which bound to both mGluRs and Homer. A search in genetic databases shows that the gene responsible for making Preso1 is present in animals ranging from fruit flies to people, highlighting its importance in a wide variety of creatures.

To figure out what Preso1 does, the researchers performed another series of experiments to examine behavior of neurons that produced both mGluRs and Homer. They found that when these neurons also expressed Preso1, the mGluRs bound Homer more efficiently, suggesting that Preso1 might somehow increase modification by protein kinases.

Worley’s team received another clue when they found that protein kinases also bind to Preso1.

Genetically modifying mice so that they don’t make any Preso1, the researchers found that binding between mGluRs and Homer in these animals’ neurons was greatly reduced compared to normal mice.

Additionally, when the researchers injected the modified mice with a chemical that causes pain and inflammation, the animals had a significantly greater and longer-lasting response compared to regular mice. A final experiment showed that neurons taken from the modified animals were significantly more responsive to the neurotransmitter glutamate. When the researchers added Preso1 to the cell cultures, this increased activity disappeared, suggesting that Preso1 is pivotal for mGluRs to signal properly.

Taken together, Worley explains, the findings suggest that Preso1 appears to gather all the important elements in this system — Homer, protein kinases and mGluRs — bringing them all together to coordinate the activation and deactivation of the mGluRs.

With Preso1 so pivotal for regulating group 1 mGluR activity, it could prove a useful new target for drugs to treat a variety of health problems in which these receptors are thought to play a role, including chronic pain, schizophrenia, Alzheimer’s disease, and fragile X syndrome, Worley says.

"Because mGluRs play so many important roles in the brain for so many different mental and neurological health conditions, knowledge of their regulatory mechanisms is extremely important. But we really don’t know how they work in great detail," he says. "You need to know all the players before you can understand the system. Here, we’ve identified an important player that no one had previously known had existed. Preso1 and Homer appear essential for desensitization of mGluR signaling, much like beta-adrenergic receptor kinase and arrestin are important for desensitization of adrenergic and opiate receptors."

Provided by Johns Hopkins University

Source: medicalxpress.com

ScienceDaily (July 17, 2012) — Johns Hopkins researchers say they have discovered a cause-and-effect relationship between two well-established biological risk factors for schizophrenia previously believed to be independent of one another.

The findings could eventually lead researchers to develop better drugs to treat the cognitive dysfunction associated with schizophrenia and possibly other mental illnesses.

Researchers have long studied the role played in the brain’s neurons by the Disrupted-in-Schizophrenia 1 (DISC1) gene, a mutation with one of the strongest links to an increased risk of developing the debilitating psychiatric illness.

In a study published in the journal Molecular Psychiatry, the laboratory of Mikhail V. Pletnikov, M.D., Ph.D., in collaboration with the laboratory of Solomon H. Snyder, M.D., D.Sc., instead looked at the role the DISC1 gene plays in glia cells known as astrocytes, a kind of support cell in the brain that helps neurons communicate with one another.

"Abnormalities in glia cells could be as important as abnormalities in neuronal cells themselves," says Pletnikov, an associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, and the study’s leader. "Most gene work has been done with neurons. But we also need to understand a lot more about the role that genetic mutations in glia cells play because neuron-glia interaction appears crucial in ensuring the brain operates normally."

Besides the paranoia and hallucinations that characterize the disease, schizophrenics have cognitive deficits, leaving them unable to think clearly or organize their thoughts and behavior.

Previous studies found that one of the roles of astrocytes is to secrete the neurotransmitter D-serine, which helps promote the transmission of glutamate in the brain, believed to be a key to cognitive function. Schizophrenics have decreased glutamate transmission. It appears, Pletnikov says, that people with DISC1 mutations associated with the psychiatric illness are faster to metabolize D-serine, which leads to a decrease in the apparently crucial transmitter.

In clinical trials, other researchers are trying to boost D-serine levels in people with schizophrenia to see if they can boost cognitive function.

In the new study, the Johns Hopkins researchers found that DISC1 is directly involved in regulating the production of D-serine by the enzyme known as serine racemase.

The researchers found that DISC1 normally binds to serine racemase and stabilizes it. The mutant DISC1 in patients with schizophrenia cannot bind with serine racemase, and instead destabilizes and destroys it. The result is a deficiency of D-serine.

The Hopkins researchers bred mice with the mutant DISC1 protein expressed only in astrocytes and, as predicted, the animals had decreased levels of D-serine. These mice also showed abnormal behavior “consistent with schizophrenia,” Pletnikov says. For example, the rodents showed sensitivity to psycho-stimulants that target glutamate transmission. By treating the mice with D-serine, the scientists were able to ameliorate the schizophrenic-like symptoms. Mice without the DISC1 mutation in astrocytes had normal D-serine levels.

Pletnikov says that in the future, researchers hope that they can target the unstable junction between the abnormal DISC1 and serine racemase. If drugs, for example, can be found to increase glutamate transmission in humans, doctors may be able to improve cognitive function in schizophrenics. He says a DISC1 mutation may also be an important risk factor in other psychiatric disorders.

"Abnormal glutamate transmission is believed to be present in patients with bipolar disorder, major depression and possibly anxiety disorders, so our findings could apply to other psychiatric diseases," he says.

Source: Science Daily

FRIDAY, July 13 (HealthDay News) — Movies often stereotype people with schizophrenia as being violent and unpredictable, says a researcher who claims Hollywood dispenses misinformation about symptoms, causes and treatment of this mental illness.

Hollywood portrayals are often inaccurate, misleading, study shows.

For the study, published in the July issue of Psychiatric Services, Patricia Owen of the psychology department at St. Mary’s University in San Antonio, Texas, reviewed 41 English-language films released between 1990 and 2010 that featured at least one main character with schizophrenia.

Owen found that 83 percent of those characters were portrayed as dangerous or violent to others or themselves. Almost one-third engaged in homicidal behavior, and one-quarter committed suicide, the researcher said.

According to the U.S. National Institute of Mental Health, the risk of violence is small among people with schizophrenia. But suicide risk is higher than average. About 10 percent, mostly young men, do kill themselves, the agency notes.

Delusions, auditory and visual hallucinations, and disorganized speech or thought were displayed by most of the characters, the study author pointed out in a news release from the American Psychiatric Association.

But much more common symptoms of schizophrenia — such as flat affect, lack of speech and lack of motivation — were seen much less frequently.

Although schizophrenia incidence is nearly equal among women and men, almost 80 percent of the characters with schizophrenia were male, the study found.

The review noted, however, the movies did get some characterizations of schizophrenia right. Specifically, about half of the characters had low socioeconomic status, which is consistent with data on the illness. Moreover, about half of the movies depicted or alluded to the use of medication to treat the mental illness. Psychotherapy and group therapy were not portrayed often.

Owen suggested that more research is needed to understand how films influence public perceptions about schizophrenia, and to determine how to increase empathy and understanding.

Films featuring a character with schizophrenia include A Beautiful Mind and Donnie Darko.

Source: DoctorsLounge