Fetal Brain Damage Leads to Schizophrenia-like Symptoms In Monkeys after the Hormonal Changes of Puberty

In studies at Yale University School of Medicine, rhesus monkeys developed schizophrenia-like symptoms as a result of selective brain damage caused by X-rays during the critical early weeks of fetal development. The monkeys tested normal on a battery of cognitive tests while growing up, but developed symptoms of hallucinations and difficulties on memory and problem-solving tests after puberty.

“This is the first evidence suggesting that schizophrenia in humans might be caused by damage to neurons in the cortex or thalamus during fetal development,” said Patricia S. Goldman-Rakic, Ph.D., professor of neurobiology at Yale. “Our study adds weight to the theory that fetal brain damage predisposes an individual to become schizophrenic after the hormonal changes of puberty. Such brain damage in conjunction with life events occurring at or around puberty may interact to allow for expression of the disease’s symptoms.”

Schizophrenia is a devastating mental disorder characterized by hallucinations, delusions, asocial behavior and cognitive deficits that often do not appear until late adolescence or early adulthood. At present, it is unclear why symptoms are not apparent until after puberty, Goldman-Rakic said, although sex hormones are known to exert a powerful influence on brain development.

The Yale study, conducted in collaboration with postdoctoral fellow Stacy Castner and reported Nov. 8 at the annual meeting of the Society for Neuroscience, demonstrated that selective loss of distinct populations of neurons resulting from X-irradiation caused behavioral deficits after puberty in all eight rhesus monkeys in the study. Furthermore, the nature and degree of impairment depended on the stages of embryonic development in which the damage occurred and the brain regions affected.

X-irradiation between 70 and 80 days of fetal development selectively depleted neurons in cerebral cortical layer III. These monkeys showed more pronounced behavior abnormalities than monkeys irradiated between 33 and 40 days of gestation, which depleted neurons in the thalamus. The timing of fetal irradiations was selected to decimate specific classes of neurons based on a detailed schedule of neurogenesis that has been worked out in primates, Goldman-Rakic said.

“Fetally X-irradiated monkeys appear to provide a useful animal model of schizophrenia,” said Castner, who added that the monkeys received either a low dose (four times with 50 Rads) or high dose of X-rays (three to six times with 100 Rads), thus depleting subcortical neurons in the thalamus or infra-granular and granular cell populations of the cortex. “The study also demonstrated that early loss of neurons may not be detected until later in life.”

She added that X-irradiation is only one way brain cells can be damaged during development. Neurons can also be deleted in the fetal brain by a number of genetic and environmental factors, such as exposure to viruses, drugs and other mutagens. The findings announced today also could be relevant to other developmental disorders, such as mental retardation and attention deficit hyperactivity disorder.

Battery of Cognitive Tests

The two groups of irradiated monkeys and aged-matched controls were tested both prior to puberty (6-18 months of age) and after puberty (3-7 years of age) on a battery of cognitive tasks, including delayed nonmatch-to-sample, spatial delayed response, visual discrimination, delayed alternation and object retrieval. (Note: Monkeys were tested on some tasks only after puberty.)

There were no significant differences between the performance of the experimental and control groups on any of the tasks before puberty. After puberty, significant impairments emerged on working memory tasks and other tests of the integrity of frontal lobe function in the irradiated monkeys compared to controls, Castner said.

Specifically, both the early and late fetally irradiated monkeys performed poorly on spatial or object tasks that tested working memory, while age-matched controls performed these tasks without difficulty. In addition, all irradiated monkeys were significantly impaired on the object retrieval task compared to controls. Some irradiated monkeys also showed symptoms of hallucinations.

“The next step in our research is to attempt to ameliorate the cognitive and behavioral deficits in the young adult monkeys suffering from schizophrenia-like symptoms,” Goldman-Rakic said. “In an effort to further explore the usefulness of the fetal X-irradiated monkey as an animal model of schizophrenia, we will attempt to reverse cognitive and frontal lobe deficits by administering chronic neuroleptics, such as clozapine or haloperidol.” Neuroleptics are commonly used to alleviate hallucinations and delusions in schizophrenics.

This research was supported by the National Institutes of Health. Other collaborators included Pasko Rakic, M.D., Sc.D., Oguz Algan, M.D., and Heather Findlay, all of Yale.

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