| 摘要: | 精神分裂症為一複雜且嚴重的精神疾病,其發病率約達整體人口 的百分之一,其常見之臨床症狀為異常的社交行為、幻覺、妄想等精神 症狀以及情緒相關行為的異常表現。目前針對精神分裂症的成因有幾個 不同的假說,包括大腦的不正常發育,神經細胞成熟調控異常以及神經 傳導物質分泌失調等;此外臨床證據顯示成年新生神經細胞在精神分裂 症患者有明顯缺損的情形,然而對於上述這些假說及神經細胞發育如何 影響精神分裂症的形成仍然尚未被研究清楚。
在本研究中,我們採用了一個病理上與精神分裂症患者最為相似 的動物模式,藉由母鼠懷孕第十七天尾靜脈注射 Poly (I:C) 模擬母體在 懷孕期間受到病毒感染,誘發免疫反應進而影響腹中胎兒之發育。藉由 在個體神經發育的不同時期(出生後三、六、九、十二週)分析多種反應 臨床上精神分裂相關症狀的動物行為模式,並搭配組織染色來分析不同 時期神經細胞的增生、分化及成熟的過程,以了解神經細胞發育如何影 響精神分裂症的發生。實驗結果顯示,Poly (I:C) 注射組的小鼠於出生 六週後開始出現多種類似精神分裂的臨床表徵,包括過度增加的空間移 動情形、異常增加的焦慮行為及認知功能缺陷。此外,藉由帶有綠色螢 光蛋白的病毒標定大腦中的新生神經細胞,我們進一步發現 Poly (I:C) 注射組的小鼠的神經細胞型態發育上有顯著地影響,而且這些神經細胞 枝幹的異常發育發生在小鼠出生後六週正好與精神分裂相關的行為表 徵有時間上的相關性。
從我們的實驗結果,我們推論在小鼠大腦中的異常神經細胞發育 (枝幹不正常增生及複雜化)對於精神分裂症的病程發展扮演著重要的 角色。這些結果提供了一個未來利用藥物來改善這些異常生長的神經細 胞將是一個臨床上治療精神分裂症的可能治療方向。
Schizophrenia is a complex and serious mental disorder that affects 1% of the global population. Patients with schizophrenia are characterized by abnormal social behavior, psychological hallucinations, and deregulated emotionality. Numerous hypotheses have been postulated toward the etiology of schizophrenia, including abnormal brain development, aberrant maturating process and neurotransmitter abnormalities. Evidence indicated that adult neurogenesis in the hippocampus is profoundly impaired in schizophrenic individuals but the role of such dysregulated neuronal developmental processing in the pathophysiological development of schizophrenia has not been well investigated.
In our current study, maternal (pregnant mice at gestation day 17) intravenous injection of poly (I:C) (a viral mimetic) was used to established a model that induce schizophrenia-like symptoms in the offspring. Numerous behavioral analyses related to the core symptoms of schizophrenia were tested at 3, 6, 9, and 12 weeks after birth. Meanwhile, the capacity of neuronal proliferation, differentiation and maturation in the schizophrenic mice were also analyzed at matched time points. We found a significant increase in schizophrenia-like behaviors in poly (I:C) group of mice which recapitulates various core psychological symptoms of schizophrenia in clinic, including hyper-locomotion, anxiety-like behaviors and cognitive impairment. Furthermore, by using a retroviral based labeling approach for monitoring of adult neuronal development in vivo, we found a significant morphological alterations of neuronal maturation process in poly (I:C) group of mice. And the aberrant development of dendritic trees and protrusions in schizophrenic brain starts at 6 weeks after birth which correlated to the onset of changes in multiple domains of schizophrenia-like behaviors.
Based on our results, we conclude that the aberrant neuronal maturation during the development is a critical determinant controlling the pathophysiological progression of schizophrenia-like symptoms. And pharmacological treatments that adjust these abnormalities may provide potential therapeutic benefits toward patients with schizophrenia in clinic. |
