Abstract
Schizophrenia is a multifactorial developmental neuropsychiatric disorder. This study examined the interplay of maternal infection and postweaning social isolation, which are prenatal and postnatal risk factors, respectively. Pregnant mice received poly I:C or saline injection on gestation day 9 and the pups were weaned at postnatal day 28. After weaning, male offspring were randomly assigned into group-rearing and isolation-rearing groups. In their adulthood, we performed behavioral tests and characterized the histochemical features of their mesocorticolimbic structures. The sociability and anxiety levels were not affected by either manipulation, but synergistic effects of the two hits on stress-coping behavior was observed. Either of the single manipulations caused defects in sensorimotor gating, novel object recognition and spatial memory tests, but the combination of the two hits did not further exacerbate the disabilities. Prenatal infection increased the number of dopaminergic neurons in midbrain, whereas postweaning isolation decreased the GABAergic neurons in cortex. Single manipulation reduced the dendritic complexity and spine densities of neurons in the medial prefrontal cortex (mPFC) and dentate gyrus. Our results support the current perspective that disturbances in brain development during the prenatal or postnatal period influence the structure and function of the brain and together augment the susceptibility to mental disorders, such as schizophrenia.
Highlights
Schizophrenia is a multifactorial developmental neuropsychiatric disorder
The two-hit hypothesis of schizophrenia had been proposed to model the pathogenic processes. It suggests that the first hit attacks the developing nervous system during the embryonic or perinatal period, and the second hit occurs during adolescence, which collectively lead to the onset of clinical symptoms [5,6,7,8]
Male offspring born to saline- or poly-inosinic/cytidylic acid (poly I):C-treated mothers were raised in groups or individually after the day of weaning, postnatal day (PD) 28
Summary
Schizophrenia is a multifactorial developmental neuropsychiatric disorder. In patients of schizophrenia, the symptoms usually emerge during adolescence to young adulthood. The two-hit hypothesis of schizophrenia had been proposed to model the pathogenic processes It suggests that the first hit attacks the developing nervous system during the embryonic or perinatal period, and the second hit occurs during adolescence, which collectively lead to the onset of clinical symptoms [5,6,7,8]. To evaluate the two-hit hypothesis of schizophrenia, temporally well-controlled manipulations of risk factors during prenatal or postnatal eras are desirable. Environmental risk factors such as prenatal infection, maternal stress, neonatal maternal separation, postweaning isolation [3,18] can be manipulated at or during a specific time period
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