September 10, 2007

New Research on DISC 1 Gene in Schizophrenia

As we've reported in the past, the gene called DISC 1 (Disrupted in Schizophrenia) has been linked to increased risk for schizophrenia. (see past stories here and here). If you have some significant biology knowledge and want to learn more about schizophrenia genetics - this might be interesting reading to you.

How the gene that has been pegged as a risk factor for schizophrenia and other mood disorders that affect millions of Americans contributes to these diseases remains unclear. However, the results of a new study by Hopkins researchers and their colleagues, appearing in the journal "Cell", provide a big clue by showing what this gene does in normal adult brains.

It turns out that the gene disc1, makes a protein that serves as a sort of musical conductor for newly made nerve cells in the adult brain, guiding them to their proper locations at the appropriate tempo so they can seamlessly integrate into our complex and intertwined nervous system. If the DISC1 protein doesn't operate properly, the new nerves go hyper.

"DISC1 plays a broader role in the development of adult nerves than we anticipated," says Hongjun Song, Ph.D., an associate professor at Hopkins' Institute for Cell Engineering. "Some previous studies hinted that DISC1 is important for nerve migration and extension, but our study in mice suggests it is critical for more than that and may highlight why DISC1 is associated with multiple psychiatric disorders."

"Almost every part of the nerve integration process speeds up," adds fellow author Guo-li Ming, M.D., Ph.D., also an associate professor at ICE. "The new nerves migrate and branch out faster than normal, form connections with neighbors more rapidly, and are even more sensitive to electrical stimulation."

While it may not be obvious why high-speed integration would be detrimental, Song notes that because of the complexity of the brain, timing is critical to ensure that new nerves are prepared to plug into the neural network.

Ming, Song and their collaborators at the National Institutes of Health and UC Davis tracked the abnormal movements of the hyperactive nerve cells by injecting a specially designed virus into a part of a mouse brain known as the hippocampus -a region important for learning and memory and therefore quite relevant to psychiatric disorders. The virus would only infect newly born cells and would both knock down the expression of the disc1 gene and make the nerves glow under a microscope.

Combined with other recent Hopkins research that successfully engineered mouse models that have abnormal DISC1 and can effectively reproduce schizophrenia symptoms such as anxiety, hyperactivity, apathy and altered senses, these current findings teasing out the normal role of this protein may help unravel the causes for this complex disease

Song and Ming add that their studies in the hippocampus - one of the few places where new nerves are made in the adult brain - might answer why symptoms typically first appear in adults despite the genetic basis of many psychiatric illnesses. They plan on continuing their mouse work to try and find those answers.

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."

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.

Note: This story has been adapted from press releases issued by Cell Press and Johns Hopkins Medical Institutions.


A question: If sz is caused by mutated gene that causes abnormal growth of nerve cells, then how come the sypmtoms of sz can be improved by taking medications? The more time people are symtpoms free and on medications, the bigger probability that symptoms will not reoccure. If the damage done by genes is permanent - how is the improvment explained?

Posted by: Marina at September 13, 2007 12:34 PM

Post a comment

Please enter this code to enable your comment -
Remember Me?
(you may use HTML tags for style)
* indicates required