自閉症類群障礙，簡稱自閉症 (Autism spectrum disorder, ASD) 為一種異質性之 神經發育的障礙。根據 Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) 定義其特徵為患者表現限制性重複行為 (restricted repetitive behavior)、社交溝通 (social communication) 及社交互動 (social interaction) 的障礙。 近年來自閉症的診斷數量大幅地提升但治療上仍不理想，凸顯其在研究上的必要性。 自閉症的病因涉及遺傳因子 (genetic factor) 及環境因素 (environmental factor) 間複 雜的相互作用。Coiled-coil and C2 domain containing 1A ( CC2D1A) 為一種高度保留 的支架蛋白，參與在多條細胞內訊息傳遞路徑中，其缺陷被證明可能參與自閉症之發 生風險。肥胖對於自閉症發生風險的增加也呈現正相關。而高脂飲食(high-fat diet, HFD)會導致體重過重、甚至引起肥胖以及代謝功能異常。雖然知悉環境與基因兩者 分別對於自閉症的發生有關，然而高脂飲食對於因基因缺陷而預先存在 (pre-existing) 的類自閉症表型 (autistic-likephenotypes) 影響為何仍有待探討。因此，此研究的主要 研究目的為探討環境因子 (高脂飲食) 與基因 (Cc2d1a) 之“雙重因子” (two-hit) 對於 自閉症發生之影響，我們提出的假設為:相較於單純 Cc2d1a 缺失導致的自閉症症狀 表現，高脂飲食會更加惡化其症狀之表現。
在此研究中，我們依照餵食正常飲食或高脂飲食、基因型的不同進行實驗分群。 小鼠自離乳後即餵食不同飲食至實驗週齡，接著進行三大類不同的類自閉症相關行為 測試。我們主要的發現為: (1) 餵食高脂飲食的雄性 Cc2d1a 基因條件性剔除小鼠， 與表現類自閉症表型缺陷的正常飲食基因條件性剔除小鼠相比，會表現更嚴重的限制 性重複行為，例如自我梳理 (self-grooming)、挖掘 (digging) 以及檢測認知僵化的滾 動/固定滾輪測試 (running / jammed wheel test); (2) 在社交行為方面也觀察到社交新 奇性 (social novelty)、相互社交互動測試 (reciprocal social interaction test)、築巢測試 (nesting test) 出現嚴重缺損的狀況， (3) 在認知相關行為方面，包含物體易位測試 (object location memory test)、新奇事物辨識測試 (novel object recognition test)、莫氏 水迷宮 (morriswatermaze) 則未觀察到有更加惡化的影響。除此之外，攝入高脂飲食 也會導致活化態的小膠質細胞 (microglia) 和星形膠質細胞 (astrocyte) 數量增加，並 加劇了海馬迴 (hippocampus) CA1 區域中錐體神經元 (pyramidal cell) 之樹突複雜性 (dendritic complexity) 和突觸小棘數量 (spine density) 的減少。此外，我們證明了透 過長期給予半合成四環素衍生抗生素之米諾環素 (minocycline) 可去緩解餵食高脂飲 食的 Cc2d1a 基因條件性剔除小鼠觀察到的行為異常以及形態缺陷。檢視與調控神經 元型態相關之訊息條傳遞路徑，我們表明 Cc2d1a 基因條件剔除性小鼠及高脂飲食會 活化 Rac1 下游之磷酸化 PAK1-3 及 Cofilin 的活性，而米諾環素處理可以降低其 活性表現。綜合以上結果，我們的研究結果顯示高脂飲食加劇預先存在的自閉症表型 及異常神經元形態，同時也證明米諾環素可緩解這些缺陷，並提供了一種可能的作用 機制來解釋高脂飲食及米諾環素的影響。

Autism spectrum disorder (ASD) refers to a broad spectrum of neurodevelopmental disorders characterized by hallmark impairments in social communication, social interaction and restricted repetitive behaviors. The etiology of ASD involves complex interactions between genetic and environmental factors. Coiled-coil and C2 domain containing 1A (CC2D1A) is an evolutionally conserved protein and regulates multiple signaling pathways. According to previous studies, dysregulation of Cc2d1a has a causal relationship with ASD. On the other hand, obesity is associate with increased risk of ASD. High-fat diet (HFD) feeding leads to overweight, obesity, and metabolic dysfunction. Although both Cc2d1a and HFD are known to be associated with ASD, the impact of HFD on pre-existing autistic-like phenotypes remains to be elucidated. Therefore, the aim of this study is to investigate the “two-hit” (genetic load × environmental factor) theory of ASD which comparing to Cc2d1a deficit model of autism, whether HFD feeding exacerbates autistic phenotypes. In this study, mice were fed with different diets starting from weaning until experimental period. Series of different autistic-like behavioral tests were then conducted. The results showed that comparing to male Cc2d1a gene conditional knockout (cKO) mice fed with normal diet, HFD cKO mice significantly increased in restricted repetitive behaviors. Results from social behavior tests also showed worsen impairment of cKO mice after HFD feeding but didn’t influence cognitive behaviors. In addition, HFD feeding led to increased activated microglia and astrocytes in hippocampus CA1 region as well as aggravated the decrease of dendritic complexity and spines density. Importantly, chronic administration of minocycline rescued the behavioral abnormalities and morphological deficits observed in Cc2d1a cKO mice fed with HFD. Finally, elevated activity of phospho-PAK1-3 and phospho-Cofilin, downstream effector of Rac1, was observed following either Cc2d1a cKO or HFD feeding, and the effect was reversed by minocycline treatment. Taken together, our findings illustrate the role of HFD in exacerbating pre-existing autism phenotypes and abnormal morphology, also demonstrate that minocycline can alleviate the deficits, and finally providing a possible potential mechanism to explain the effects of HFD and minocycline.

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