A gene with reported links to schizophrenia and other mood disorders plays a broader role in the brain than scientists had previously suspected, according to a report published online by Cell, a publication of Cell Press, on September 6, 2007.
The study reveals that the gene, known as Disrupted-In-Schizophrenia 1 (DISC1), directs the incorporation of new neurons into the adult brain and keeps the process under control. The gene's newly discovered roles might help to explain why schizophrenia's symptoms generally arise in adolescence or early adulthood, the researchers suggested.
The research team found that mice with reduced DISC1 levels in just a few new brain cells showed accelerated integration of those neurons into the existing brain circuitry. The abnormally shaped neurons that resulted from the flurried activity also wound up positioning themselves improperly. What's more, the DISC1-deficient newborn neurons were increasingly excitable and developed a greater number of junctions, or synapses, with other brain cells.
"Everything is happening faster than it's supposed to happen," said Guo-li Ming of Johns Hopkins University School of Medicine.
"Normally, new neurons migrate within certain ranges, but cells with reduced DISC1 overshoot and end up in the wrong place," added Hongjun Song, also of Johns Hopkins. "They also grow a lot more dendritic processes and fire at a faster rate. Synapse formation is much faster. A series of things go wrong, and everything is sped up. It appears that they just can't stop somehow." Dendritic processes are the branches found at neurons' receiving ends.
"This study reveals two unexpected functions of DISC1 [in the adult brain]: regulation of synapse formation and neuronal firing," said study collaborator Bai Lu of the National Institute of Mental Health, adding that abnormalities of those neural functions have been implicated in the pathogenesis of schizophrenia.
The exact consequences of the new brain cells' fast-paced behavior aren't yet clear, the researchers said. Indeed, the functional role of neurons that are born during adulthood, a process known as adult neurogenesis, remains open to question. However, some studies have suggested that the newborn neurons are important for learning and memory--playing a possible role in song birds' ability to learn new tunes, for example, Ming added. Adult neurogenesis has also been implicated in mood disorders such as depression, Lu said.
Schizophrenia is a chronic, severe, and disabling brain disorder that affects about 1 percent of Americans, according to the National Institute of Mental Health. People with the condition may hear voices or believe others are plotting against them.
Mutations in the gene encoding DISC1 had been linked to schizophrenia and other mood disorders, including depression and bipolar disorder, in multiple family pedigrees, the researchers said. Yet, the neurobiology of the DISC1 protein in the normal developing and adult brain and its roles in these mental illnesses haven't been well understood.
DISC1 was known to be active in many brain regions during embryonic development. But in the adult brain, the gene is active only in a few restricted areas, including certain cells of the hippocampus. That brain region is important for learning and memory and mood control. Studies in cell culture and in embryonic brain tissue have also provided evidence that neurons with reduced amounts of the protein display impaired growth of neuronal processes and stunted migration.
To find out what the gene does in live animals in the current study, the researchers used a unique strategy they developed to manipulate the gene's activity in individual adult neural stem cells within the hippocampuses of adult mice.
"In vivo, DISC1 does more than expected, regulating many processes essential for establishing a network for brain function. We were also surprised to find that the gene does something different in the adult brain than what it seems to do in embryonic stages," Song said.
"It appears that you need tight regulation of DISC1 levels for new neurons to integrate into the brain circuitry properly," Lu said. A decrease in DISC1 levels during development may result in earlier and abnormal formation of neuronal circuitry, leading to abnormal brain function in the adult, he added.
Just what the new findings in mice will mean for people with schizophrenia and other mental illnesses linked to the gene remains unknown, but they do point to some tantalizing possibilities, according to the researchers.
"It's been an intriguing question why a developmental disease like schizophrenia would have an adult onset," Song said, noting that the condition normally strikes people at the age of 20 or older. "Our findings raise the possibility that a defect in the generation of new neurons specifically in the adult brain might contribute. We don't have the answer yet, but we do now have the suggestion."
Xin Duan of Johns Hopkins University School of Medicine in Baltimore; Jay H. Chang of National Institute of Mental Health, National Institutes of Health in Bethesda; Shaoyu Ge of Johns Hopkins University School of Medicine in Baltimore; Regina L. Faulkner of University of California, Davis in Davis; Ju Young Kim and Yasuji Kitabatake of Johns Hopkins University School of Medicine in Baltimore; Xiao-bo Liu of University of California, Davis in Davis; Chih-Hao Yang, J. Dedrick Jordan, Dengke K. Ma, and Cindy Y. Liu of Johns Hopkins University School of Medicine in Baltimore; Sundar Ganesan of National Institute of Mental Health, National Institutes of Health in Bethesda; Hwai-Jong Cheng University of California, Davis in Davis; Guo-li Ming of Johns Hopkins University School of Medicine in Baltimore; Bai Lu of National Institute of Mental Health, National Institutes of Health in Bethesda; and Hongjun Song of Johns Hopkins University School of Medicine in Baltimore.
This work was supported by NIH (NS047344 and AG024984) and McKnight Scholar Award to H.S. by NIH (NS048271), Whitehall Foundation, and a Klingenstein Fellowship Award in the Neurosciences to G-l.M. and by NIH (HD045757) to H-j.C.
Reference: Duan et al.: "Disrupted-In-Schizophrenia 1 Regulates Integration of Newly Generated Neurons in the Adult Brain." Publishing in Cell 130, 1--13, September 21, 2007. DOI 10.1016/j.cell.2007.07.010
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