以思覺失調症候選基因Akt1缺陷小鼠探討新生期聚肌胞苷酸刺激對新生期免疫反應與成鼠行為之影響

Abstract

Schizophrenia appears to be a multifactorial disorder with a strong genetic predisposition. Accumulating evidence suggests Akt1 (also known as protein kinase Bα) may contribute to susceptibility to schizophrenia. Akt1 knockout mice also exhibited some behavioral impairments and neuromorphological abnormalities. In addition to genetic predisposition, early infection-induced disruption in neurodevelopment may lead to functional deterioration and the onset of schizophrenia in later life. Indeed, immuno-precipitated neurodevelopmental animal models displayed aberrant behavioral functions. An alteration of Akt1 expression was also observed in prenatal immune challenged mice. Given the existing evidence, the objective of this study is to examine the effect of early infection alone and its interaction with Akt1 deficiency on the alterations of neonatal immune responses and schizophrenia-related neurobehavioral functions in adulthood. Akt1 heterozygous pups and their wild-type littermate controls received daily injections of polyriboinosinic-polyribocytidylic acid (poly(I:C)) from postnatal days 2 to 6 to induce antiviral responses. Their neonatal immune responses and adult behavioral consequences were evaluated in three experiments. In Experiment 1, using a cytometric bead array, our cytokine analysis revealed an alteration of TNF-α level in female Akt1 deficient pups compared to wild-type controls after poly(I:C) challenge. In Experiment 2, Iba1 immunohistochemistry was used to label microglia in the mouse brains. Our data exhibited an enlargement of microglia size or an increased expression of Iba1+ cell numbers in Akt1-deficient neonatal mice with neonatal poly(I:C)-challenge, especially in the thalamus and the periaqueductal gray region of female mice. In Experiment 3, a battery of behavioral tasks, including open field, Y maze, social preference, social recognition, USVs playback approaching paradigm, tail suspension, and prepulse inhibition, were conducted in adult mice three months after neonatal poly(I:C) challenge. The overall behavioral phenotyping results indicated that neonatal poly(I:C) challenge appeared to have minor long-term impacts on behavioral performances. A sex-specific interaction between genotype and poly(I:C) challenge in social recognition was found in adult male mice. We also found that Akt1 deficient females with neonatal poly(I:C) challenge also displayed an impairment of sensorimotor gating function. Our data indicated that neonatal poly(I:C)-induced immune response can be altered by Akt1 deficiency but neonatal poly(I:C) exposure has minor impacts on adult behavioral performance. This study suggested a possible association among Akt1, TNF-α and microglia in the pathogenesis of schizophrenia-related phenotypes.