Early disruption of schizophrenia gene causes problems later

SAN DIEGO — Disrupting a gene implicated in schizophrenia early in development leads to brain anomalies and behavioral defects later in life, a new study in mice finds. The results, presented February 22 at the annual meeting of the American Association for the Advancement of Science, may help researchers understand how early developmental problems contribute to schizophrenia — a disease that typically shows up after adolescence.

In humans, mutations in a gene called DISC1 cause flaws in networks of brain cells early in development, scientists believe, long before symptoms of schizophrenia appear. Researchers led by Akira Sawa of Johns Hopkins University School of Medicine in Baltimore developed a new technique to diminish DISC1 activity in mice that are still developing in the womb. The method temporarily reduces DISC1 activity in brain cells in the mice’s prefrontal cortex, a region known to be important for schizophrenia.

Sawa and colleagues disturbed DISC1 very early in development and tested the mice later. The mice’s brain chemistry and behavior seemed normal at 28 days. But at 56 days, Sawa and colleagues saw a big change. “After adolescence, we start to observe a dramatic difference in behavior, neurochemistry and information processing,” Sawa says.

Mice that had reduced DISC1 activity in the womb had lower levels of dopamine in the prefrontal cortex at 56 days, the team found. DISC1 might be interfering with the normal development of dopamine-producing neurons, leading to the reduction of the chemical signal, Sawa says. What’s more, these mice performed worse on behavioral measures that require information processing.

In further experiments, the researchers treated the mice with a drug called clozapine, which elevates dopamine levels and is used to treat schizophrenia in people. After treatment, the mice showed reduced behavioral defects. The results give researchers hope that interventions at the adult stage can overcome deficits incurred early in development, Sawa says.  

Psychologist Tyrone Cannon of the University of California, Los Angeles calls Sawa’s research “critical and elegant work.” Although scientists have known for over 50 years that disorders like schizophrenia are highly heritable, “it’s taken us quite a bit of time to realize just how complex the genetic architecture of these disorders is, and to develop strategies that can begin to unravel the mystery of their inheritance,” he says.