思覺失調症候選基因Akt1與neuregulin 1的交互作用
對於小鼠社會行為的影響

從人類遺傳學累積的研究證據顯示有若干候選基因可能對於思覺失調症的病因有著重要的影響，包含AKT1 及NRG1。最近的研究也指出，經由NRG1刺激ErbB2/4接受器活化PI3K/AKT 訊息傳導，在思覺失調症的行為缺損中扮演著重要的角色。善用基因剃除小鼠的研究模式，可以直接檢驗Akt1/Nrg1基因單獨及雙重變異小鼠還有它們的同窩野生控制組小鼠之間的差異，進而用來探討Akt1/Nrg1基因之間的交互作用對於認知行為及社會行為的影響。本研究共包含三個主要的實驗。在實驗一中，研究發現，基因雙重變異小鼠體重與其他三組沒有明顯差異。然而，Akt1基因單獨變異及雙重變異的小鼠在紋狀體及背側海馬迴這兩個腦區，則表現出比較低的腦部活動。在實驗二中，小鼠基本行為的檢測結果並未發現有任何明顯地基因變異所造成的影響，包含自發性運動行為、類焦慮行為以及感覺動作反射。在認知行為作業中，則發現Nrg1基因單獨變異及雙重變異的小鼠，會表現出類事件記憶的缺損。在社會行為測試中，只發現有基因雙重變異的小鼠會表現出明顯地社交畏縮的行為。實驗三中，Akt1/Nrg1基因之間的協同作用則進一步在基因雙重變異的小鼠身上得到確認。特別是它們在與成年雄性之間以及與卵巢切除母鼠間的互動，都表現出明顯地社交畏縮行為。另一方面，Nrg1基因單獨變異及雙重變異的小鼠，在母鼠尿液刺激下，則發出比較少的超聲波。總結來說，本研究的實驗結果揭露了Akt1/Nrg1基因的雙重變異對於社會認知功能的影響，而這樣的影響可能是造成思覺失調症相關的社會功能缺損的病因之一。

關鍵字

Akt1 ； Nrg1 ；基因雙重剃除小鼠；思覺失調症；基因交互作用；小鼠行為作業；小鼠社會行為

並列摘要

An accumulation of evidence from human genetic studies has suggested several functional candidate genes for the susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 acts through ErbB2/4 in a paracrine fashion to stimulate the PI3-kinase/AKT signaling pathway, which might be involved in the functional deficiencies of the schizophrenic. To build our model, we controlled and bred Akt1/Nrg1 single and double mutant mice and their wild-type littermate controls. We used these mice to examine the epistasis effect of Nrg1 and Akt1 on the regulation of behavioral phenotypes, cognition, and social functions. We conducted a set of three experiments in this study. In Experiment 1, double mutant mice displayed a normal profile of bodyweight during development, whereas Akt1+/- and double mutant mice displayed lower brain activity in the striatum and dorsal hippocampus, as per microPET scan results. In Experiment 2, we found no significant genotypic differences in our basic behavioral phenotying, including locomotion, anxiety-like behavior, and sensorimotor gating. However, both double mutant mice and Nrg1+/- mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other three groups, a result especially significant when these mice encountered a novel male or an ovariectomized female. Double mutant mice and Nrg1+/- mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognitions.

並列關鍵字

Akt1 ； neuregulin 1 (Nrg1) ； double mutant mice ； schizophrenia ； epistatic effect ； behavioral phenotyping ； social interaction ； social communication

參考文獻

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思覺失調症候選基因Akt1與neuregulin 1的交互作用對於小鼠社會行為的影響

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