| A great deal of evidence suggests that at least some fraction of schizophrenia is caused by errors in fetal development, probably originating in the sixth month of pregnancy and possibly involving stress to the mother. To test the fetal developmental hypothesis of schizophrenia, I have stressed pregnant rats at a critical stage of development and examined the behavior and neuroanatomy of the resulting pups when they reach young adulthood. In three major experiments carried out over three years, pregnant Wistar strain rats were stressed by either immobilization, shaking, or injections of isotonic saline. Stressors were applied once each day at 10am on days e11--e14 inclusive of gestation. Litters were culled to 8 animals of mixed sex within 48 hr of birth. At day p22 the pups were weaned and housed in pairs of the same sex and same treatment group. Pups were tested for prepulse inhibition of the acoustic startle response and for open field behavior at various ages, and were sacrificed for neuroanatomical evaluation at ages between p45 and p105. The puberty of this strain of rats occurs between p55 and p65. Prepulse inhibition is reduced in the treated animals. The reduction is noticeable at ages > p36, but becomes consistantly significant only at ages >p70 (p < 0.05). In a similar manner, increased rearing in the open field is significant, but only at ages >p82. These changes suggest a spontaneously occurring hyperdopaminergia which becomes manifest only after puberty. In this sense, the behavioral data mimic those seen with human schizophrenics. Anatomical studies show moderately increased disorganization of hippocampal pyramidal cells (p = 0.065) in the PS/CA1 interface in stressed animals. For both behavioral and neuroanatomical measures, short times of immobilization (30--120 sec) were more effective than longer ones (300 sec). These data suggest that rats treated with mild but not severe prenatal stress are similar to schizophrenics, providing evidence to support the fetid developmental hypothesis. Prenatally stressed rats may provide a model with construct validity for the human disease. |
