Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, No. 388, Jianshe Middle Road, Xinxiang, 453002, Henan, People's Republic of China.
Henan Key Lab of Biological Psychiatry of Xinxiang Medical University, Xinxiang, China.
Behav Brain Funct. 2019 Mar 5;15(1):3. doi: 10.1186/s12993-019-0154-2.
Maternal immune activation (MIA) during gestation can increase the later risk of schizophrenia in adult offspring. Neuroinflammation is believed to underlie this process. Postmortem brain studies have found changes in the neuroimmune systems of patients with schizophrenia. However, little is known about the dynamic changes in cerebral inflammation and behavior during the course of the disease.
Here, the prepulse inhibition (PPI) test was conducted in adolescent and adult Sprague-Dawley rats prenatally challenged with polyriboinosinic-polyribocytidylic acid (Poly I:C) on gestational day 9 to determine the behavioral trajectory triggered by early exposure to Poly I:C. Brain immune changes were determined in the prefrontal cortex (PFC) and hippocampus (HC) at both ages. The status of the microglia and astrocytes was determined with immunohistochemical staining. The levels of IL-6, IL-1β, and TNF-α in both brain regions were evaluated with enzyme-linked immunosorbent assays.
Disrupted PPI, the core phenotype of schizophrenia, only emerged in adulthood. Behavioral changes during puberty and adulthood were both accompanied by the activation of microglia (PFC and HC). Astrocytes were only activated at PN60. The levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) in the offspring of the Poly I:C-exposed mothers differed with brain region and time, with more cytokines elevated during periadolescence than during adulthood.
Our findings indicate that immune activation emerged before symptom manifestation in the offspring of MIA rats. We conclude that early prenatal Poly I:C challenge can lead to age-related behavioral and neuroinflammatory changes. These data provide new insight into the neuroinflammatory and neuropathological mechanisms underlying the development of schizophrenia. They also suggest that periadolescence could be more important than adulthood in the prevention and treatment of schizophrenia.
妊娠期间母体免疫激活（MIA）会增加成年后代患精神分裂症的风险。神经炎症被认为是这一过程的基础。尸检脑研究发现精神分裂症患者的神经免疫系统发生了变化。然而，对于疾病过程中大脑炎症和行为的动态变化知之甚少。
本研究采用聚肌胞苷酸（Poly I:C）在妊娠第 9 天对 Sprague-Dawley 大鼠进行产前挑战，通过预脉冲抑制（PPI）试验来确定早期暴露于 Poly I:C 所引发的行为轨迹，以确定行为轨迹。在青少年和成年时，分别在额皮质（PFC）和海马（HC）中检测大脑免疫变化。用免疫组织化学染色法确定小胶质细胞和星形胶质细胞的状态。用酶联免疫吸附试验评估两个脑区的 IL-6、IL-1β 和 TNF-α 水平。
精神分裂症的核心表型——PPI 破坏仅在成年期出现。青春期和成年期的行为变化都伴随着小胶质细胞的激活（PFC 和 HC）。星形胶质细胞仅在 PN60 时被激活。母体 Poly I:C 暴露后代的促炎细胞因子（IL-1β、IL-6 和 TNF-α）水平因脑区和时间而异，青春期比成年期有更多的细胞因子升高。
我们的研究结果表明，免疫激活出现在 MIA 大鼠后代出现症状之前。我们得出结论，早期产前 Poly I:C 挑战会导致与年龄相关的行为和神经炎症变化。这些数据为精神分裂症发展的神经炎症和神经病理学机制提供了新的见解。它们还表明，青春期比成年期在精神分裂症的预防和治疗中更为重要。
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