Interplay of Prenatal and Postnatal Risk Factors in the Behavioral and Histological Features of a "Two-Hit" Non-Genetic Mouse Model of Schizophrenia.

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.

Characterization of striatal phenotypes in heterozygous Disc1 mutant mice, a model of haploinsufficiency.

Disrupted-in-Schizophrenia 1 (DISC1) is a susceptibility gene for several psychiatric illnesses. To study the pathogenesis of these disorders, we generated Disc1 mutant mice by introducing the 129S6/SvEv 25-bp deletion Disc1 variants into the C57BL/6J strain. In this study, we used heterozygous Disc1 mutant (Het) mice to evaluate the DISC1 haploinsufficiency model of schizophrenia. No changes in locomotor behaviors were observed in Het mice; however, after amphetamine injection, greater locomotor activity was observed in Het mice compared with wild-type (WT) mice. Moreover, amphetamine-induced elevations of c-Fos expression and dopamine level in the striatum were greater in Het mice than in WT controls, suggesting an altered dopaminergic regulation in the striatum of Het mice. Compared with those in WTs, the striatal protein levels of dopamine transporter and D2 dopamine receptor were increased in Het mice, while D1 dopamine receptor level was decreased. DISC1 interacting proteins, GSK3α and GSK3ß, were downregulated in Het mice, whereas the levels of PDE4B and CREB were not altered. Morphologically, the complexities of striatal median spiny neurons (MSNs), parvalbumin-positive interneurons and Iba1-positive microglia were all decreased in Het mice. The density and head diameter of dendritic spines in the MSNs of Het mice were also reduced. Our results indicate that mice lacking one WT Disc1 allele are more sensitive to psychostimulant amphetamine challenge, which might be attributed to the altered structure and function of the striatal dopaminergic system. Here, we demonstrated striatal phenotypes in heterozygous Disc1 mutant mice, which could be a promising model of DISC1 haploinsufficiency.

Prenatal infection affects the neuronal architecture and cognitive function in adult mice.

Environmental factors such as prenatal infection are involved in the pathogenic processes of neurodevelopmental psychiatric disorders. In the present study, we administered a viral mimic, polyriboinosinic-polyribocytidylic acid (poly I:C, 20 mg/kg, i.p.), to pregnant B6 mice at gestational day 9.5. Neonates born to these poly I:C-treated dams showed an increase of microglia in the hippocampus, indicating an activation of the immune system in the brains. Moreover, a significant increase in the number of dopamine-producing neurons in the ventral tegmental area was observed in adult male poly I:C offspring compared with age-matched saline offspring. Poly I:C offspring also exhibited hypolocomotor activity in a novel open-field arena but did not display signs of anxiety or depression in the elevated plus maze or the forced swim test, respectively. However, the short-term memory of the poly I:C offspring was impaired in a novel object recognition task. Therefore, the dendritic architecture of granule cells in the dentate gyrus (DG) and pyramidal neurons in the medial prefrontal cortex (mPFC) were examined. The dendritic complexity was reduced in the DG granule cells of the poly I:C offspring and exhibited shorter dendritic length compared with the saline offspring. The density of dendritic spines in the DG granule cells was also decreased in the poly I:C offspring. Furthermore, the dendritic complexity and spine density were reduced in layer II/III mPFC pyramidal neurons of the poly I:C offspring. Together, these data demonstrate impaired short-term memory and altered dendritic architecture in adult poly I:C offspring, which validates the prenatal infection paradigm as a model for neurodevelopmental psychiatric disorders.