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Second DISC-1 Study Suggests Reason for Adolescent Onset of Schizophrenia

In a second study, researchers at Johns Hopkins and collaborating institutions have identified a mechanism whereby alterations in the DISC-1 (disrupted in schizophrenia-1) gene may underlie the adolescent onset of schizophrenia. In this second study, published in the March issue of Nature Neuroscience, the research team examined DISC-1's role in forming connections between nerve cells. The first study looked at the long-term effects of transient DISC-1 gene expression changes near the time of birth in a mouse model. This first study was published in the February 25, 2010 issue of Neuron and has previously been reported on in BioQuick News. Taken together, the results of both studies suggest that anatomical differences that seem to be influenced by the DISC-1 gene cause problems that start before birth, but surface only in young adulthood. "If we can learn more about the cascade of events that lead to these anatomical differences, we may eventually be able to alter the course of schizophrenia. During adolescence, we may be able to intervene to prevent or lessen symptoms," said second study senior author and first study co-author Dr. Akira Sawa, professor of psychiatry and director of the program in molecular psychiatry at the Johns Hopkins University School of Medicine. Numerous studies have previously suggested that schizophrenia results from abnormal connectivity. The fact that symptoms typically arise soon after adolescence, a time of massive reorganization of connections between nerve cells, supports this idea. The scientists began their second study by surveying rat nerve cells to see where DISC1 was most active. Unsurprisingly, they found the highest DISC-1 activity in connections between nerve cells.

To determine what DISC-1 was doing in this location, the researchers used a technique called RNA interference to partially shut off DISC-1 activity. After doing this, they saw a transient increase and eventual reduction in the size and number of dendritic spines, which are spikes on nerve cells' branch-like extensions that receive input from other nerve cells.

To determine how DISC-1 regulates dendritic spine formation, the researchers studied which brain proteins interact with the protein expressed by the DISC-1 gene. They identified one such protein, called Kal-7, which earlier studies had suggested is critical for proper dendritic spine formation. Further experiments suggested that the DISC-1 protein acts as temporary holding place for Kal-7, binding it until it can be released to trigger a molecular cascade that results in dendritic spine formation.

Dr. Sawa said it is becoming clear that having a defective DISC-1 gene might lead to an abnormally small number and size of dendritic spines, which could lead nerve cells to maintain weaker connections with unusually low numbers of neighboring neurons. Such abnormal connectivity has long been seen in autopsied brains from schizophrenia patients.

"Connections between neurons are constantly being made and broken throughout life, with a massive amount of broken connections, or 'pruning,' happening in adolescence," Dr. Sawa said. "If this pruning doesn't happen correctly, it may be one reason for the pathogenesis of schizophrenia," he added.

In the first of the two studies suggesting connections between DISC-1 and the adolescent onset of schizophrenia, a team including Dr. Sawa showed that a transient reduction of DISC-1 gene expression in the mouse prefrontal cortex just before or after birth led to aberrant changes in adult animals that are associated with schizophrenia--including perturbation of specific dopaminergic brain pathways, disruption of neural circuitry, and severe behavioral abnormalities. [Press release] [Nature Neuroscience abstract] [Neuron abstract] [Previous BioQuick News article]