New Frontiers in Schizophrenia and Bipolar Disorder Research

author: Edward Scolnick, Broad Institute
published: Oct. 7, 2010,   recorded: May 2009,   views: 4780

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In contrast to cardiovascular disease, few breakthrough remedies for psychiatric illness have emerged in the past half century. Edward Scolnick lays blame for this dismal situation on barriers to understanding the genetic basis behind such illnesses. But the research drought may be over, as the current revolution in human genetics opens wide a door into the molecular biology and brain physiology behind diseases like schizophrenia and bipolar disorder.

These common, chronic and disabling mental illnesses are complex, involving abnormal behaviors that vary in expression. They have also lacked the kind of quantitative tests that enable precise diagnosis. While science has demonstrated that the single biggest risk factor for both schizophrenia and bipolar disorder is genetic, it has not been able to design tools for exploring how the genetics relates to the evolution of the disease in people. But just in the last two years, with the sequencing of the human genome and maps of human genetic variation, ignorance has given way to major findings.

In schizophrenia and bipolar disease, researchers have discovered that gene deletions and duplications (called copy number variants) cause significant brain circuit mischief. They’ve also learned there are gene variants common to both diseases, as well as clusters of genes that malfunction. Scolnick describes diverse research at MIT, proceeding at a “breakneck pace,” that uses this genetic information “to delve into the malfunctioning of brain circuits.”

Scientists have applied functional magnetic resonance imaging to compare the brains of ordinary people and schizophrenia patients, and discovered that the schizophrenic’s brain in a resting state is hyperactive. Other researchers found that schizophrenics generate the gamma brainwaves involved with higher mental activities in a different manner than control subjects.

Another MIT lab has begun to manipulate specific brain circuits using optical technology -- shining different wavelengths of light at special interneurons that regulate the firing of other neurons, and which are postulated to have a critical role in the malfunctioning of schizophrenics’ brains. Two other MIT labs are examining the biochemical disruptions due to altered genes, and developing “safe, specific chemical inhibitors” that might yield potential treatments for schizophrenia and bipolar illnesses. In Japan, researchers are growing stem cells into brain cells, which may lead to precise experiments that relate genetic problems to malfunctions in brain wiring. Indeed, adding up this research, a central biochemical pathway central to the pathogenesis of psychogenic illness seems to be emerging, knowledge that “can be exploited to understand illness and to find drug treatments.”

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