Vol. 9, No. 3, 2003 Page 1&3


By investigating the genes of animals, researchers are gaining new insights into the influence of genes on the mental disorders that plague humans. In particular, new studies reveal the strong role that genes play in schizophrenia, depression, aggression, and anxiety. Among recent findings:

Suspected schizophrenia gene identified

It's likely that more than a dozen genes affect your chances of developing schizophrenia, but Susumu Tonegawa and colleagues recently discovered a gene that may contribute to a large percentage of cases of the disease. Studying short-term memory in mice, they created "conditional knockout" mice genetically altered to lack calcineurin (an enzyme involved in memory) in their forebrains. The mice exhibited specific memory deficits much like those seen in humans with schizophrenia, and also developed schizophrenia-like behaviors, including extreme withdrawal.

To determine the relevance of this finding to humans, Tonegawa collaborated with Maria Karayiorgou to see if they could link any calcineurin-related gene to schizophrenia. Studying 410 families with histories of schizophrenia, they identified a specific haplotype (closely related variants of a gene, generally inherited as a unit) of a gene called PPP3CC—which codes for a subunit of calcineurin—in 38 percent of parents of schizophrenics. This haplotype was transmitted to children with schizophrenia significantly more often than would be predicted by chance. Moreover, it occurred on chromosome 8, which already is strongly linked to schizophrenia.

Karayiorgou says the findings indicate that a disruption in calcineurin signaling may be a powerful contributor to schizophrenia, and that this discovery could lead to more effective treatments targeted at this enzyme.

Stress-linked depression:
candidate gene pinpointed

Many people thrive even when their lives become highly stressful, while many others develop depression in response to chronic stress. Laboratory research shows that the same is true of some animals, and that the brain chemical serotonin plays a role in this phenomenon.

In 2000, researchers reported that knockout mice lacking the serotonin transporter gene (5-HTT), which is involved in "recycling" serotonin after it is released into the synapses between neurons, behaved normally in the absence of stress but became unusually fearful and developed elevated levels of stress-related hormones when placed in stressful situations. Similarly, rhesus macaques bred to carry a short version of the serotonin transporter gene exhibited impaired serotonin function when raised in stressful conditions, but not when raised in normal environments.

To determine if these findings translated to humans, Avshalom Caspi, Terrie Moffitt and colleagues recently examined data from 847 New Zealanders participating in a large-scale study. Of the group, 17 percent carried two copies of the "stress sensitive" short version of the 5-HTT gene, 31 percent carried two copies of the "stress protective" long variant, and 51 percent had one copy of each gene.

The researchers narrowed their study group to people who had suffered multiple stressful life events between the ages of 21 and 26. Among this group, the researchers found, 43 percent of those with two copies of the short variant developed depression, compared to 17 percent of those with two copies of the long variant. (Subjects with one long and one short variant had an intermediate risk.) Moreover, among subjects who experienced multiple stressors, 11 percent with two short gene variants contemplated or attempted suicide, compared to 4 percent with two long gene variants.

These findings, the researchers say, provide "evidence of a gene-by- environment interaction, in which an individual's response to environmental insults is moderated by his or her genetic makeup."

"Super-aggressive" knockout
mice created

Earlier this year, Evan Deneris and colleagues reported that in knockout mice missing a gene called Pet-1, most neurons critical to serotonin function fail to develop at all, and remaining neurons are defective. Another group of researchers led by David Sweatt initially designed a study to investigate these mice for possible memory deficits, but switched gears when they discovered that the Pet-1 knockout mice were remarkably vicious and anxious.

"It was shocking how aggressive they were," Sweatt said. "None of us has ever seen anything like it before.... they were really mean."

In addition, Sweatt and his colleagues found, the mice were highly anxious, huddling at the sides of a test chamber rather than eventually wandering out like normal mice. Says Deneris, "The behavior of Pet-1 knockout mice is strikingly reminiscent of some human psychiatric disorders that are characterized by heightened anxiety and violence."

He adds, "This is the first gene shown to impact adult emotional behavior through specific control of fetal serotonin neuron development."


"Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit," D. J. Gerber, D. Hall, T. Miyakawa, S. Demars, J. A. Gogos, M. Karayiorgou, and S. Tonegawa, Proceedings of the National Academy of Sciences, Vol. 100, No. 15, July 22, 2003, 8993-8. Address: M. Tonegawa, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.

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"New clues to schizophrenia come from mice, humans," news release, Rockefeller University, June 30, 2003.

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"Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene," Avshalom Caspi, Karen Sugden, Terrie E. Moffitt, Alan Taylor, Ian W. Craig, HonaLee Harrington, Joseph McClay, Jonathan Mill, Judy Martin, Anthony Braithwaite, and Richie Poulton, Science, Vol. 301, No. 5631, July 18, 2003, 386-9. Address: Terrie Moffitt, t.moffitt@iop.kcl.ac.uk.

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"Gene more than doubles risk of depression following life stresses," news release, National Institute of Mental Health, July 17, 2003.

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"Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior," T. J. Hendricks, D. V. Fyodorov, L. J. Wegman, N. B. Lelutiu, E. A. Pehek, B. Yamamoto, J. Silver, E. J. Weeber, J. D. Sweatt, and E. S. Deneris, Neuron, Vol. 37, No. 2, January 23, 2003, 233-47.

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"'Mad mice' provide unique model to study anxiety, hyper- aggression," Anissa Anderson Orr, Baylor College of Medicine newsletter, March 2003.

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"Researchers discover anxiety and aggression gene in mice," news release, Case Western Reserve University School of Medicine, January 23, 2003.

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