| Abstract: | Understanding the Neural Basis of Psychomotor Symptoms in Rett Syndrome: the Role of the Developing Striatum 探索瑞特氏症心理運動失調之神經基礎: 發育中紋狀體的角色瑞特氏症 (Rett Syndrome, RTT) 是一種發展遲緩型心智障礙，其症狀特徵為在出生後6-18 個月後逐漸失去語言能力及目標導向之運動技能，接著出現手部絞動之刻板行為，行動困難及自閉傾向。大部分的RTT 病例是肇因於X 染色體上製造甲基CpG 結合蛋白2 (MeCP2)的基因發生偶發性突變。 MeCP2 蛋白缺失之小鼠可重現主要的RTT 症狀。無論是在RTT 患者或模式小鼠，心理運動失調均為發作早期之典型症狀，顯示MeCP2 蛋白缺失所造成之神經細胞病變可能發生在腦部發育的早期。然而，在RTT 的致病機轉中, 神經功能病理損傷發生的時間窗以及心理運動失調所涉及的腦部區域則尚未被詳細地探討。我們最近發現在MeCP2 缺失的小鼠，其紋狀體中多巴胺訊息傳遞分子的表現量有明顯的改變。除此之外，這些小鼠的運動學習能力也明顯較差。由於紋狀體在運動與認知功能的控制扮演重要的角色，因此我們假設RTT 之心理運動失調主要是由於發育中的紋狀體受到干擾而產生異常所致。本計畫中，我們打算結合分子、細胞與行為的方法，有系統地分析MeCP2 缺失小鼠之發育中紋狀體的表型特徵。首先，我們將針對不同發育時期探討紋狀體中多巴胺訊息傳遞分子的基因表現，紋狀體區間分隔結構的形成，以及進出紋狀體之投射神經纖維的分佈走向。接下來我們將利用遺傳學的方法進行區域專一性的研究，將MeCP2 從正常小鼠之紋狀體移除，或是在MeCP2 缺失小鼠的紋狀體重新表現MeCP2，並分析這些條件式基因操弄小鼠之心理運動行為及不同發育時期之紋狀體表型特徵。本研究之目標在於探討並了解MeCP2 如何參與控制紋狀體的發育，以及紋狀體的發育在RTT 心理運動功能失常所扮演的角色。我們希望這個研究計畫將不只提供RTT 心理運動失常之神經病理學基礎，也能夠藉由釐清RTT 心理運動失常的相關腦區、神經傳導物質系統和發育早期異常的時間窗，有效促進RTT 心理運動症狀的早期療癒。
Understanding the Neural Basis of Psychomotor Symptoms in Rett Syndrome: the Role of the Developing Striatum (探索瑞特氏症心理運動失調之神經基礎: 發育中紋狀體的角色) Rett syndrome (RTT) is a developmental psychiatric disorder, characterized by progressive lose of acquired language ability and goal-directed motor skills after the first 6-18 months of life, and followed by stereotypical hand-wringing, ataxia, and autistic behaviors. Most of the RTT cases are caused by sporadic mutations in the X-linked gene encoding methyl CpG binding protein-2 (MeCP2). Mice lacking functional MeCP2 recapitulate the majority of RTT symptoms. The early onset of characteristic psychomotor deficits in both patients and RTT mouse models suggests that the pathological neuronal insults caused by MeCP2 deficiency may occur during early brain development. However, the developmental time window when pathogenic damages of neural function occur, and particularly, the responsible brain region for the psychomotor deficits have yet to be identified. We recently found that the dopamine signaling molecules are significantly altered in the striatum of MeCP2 deficient mice. In addition, these mice showed significantly impaired motor learning skill. Given that the striatum is known to play a pivotal role in the control of motor and cognitive functions, we hypothesize that the developing striatum may be the primary affected neural substrate for the psychomotor deficits in RTT. In this proposal, we plan to characterize the striatal phenotypes of MeCP2 deficient mice with a combination of molecular, cellular, and behavioral approaches. We will specifically examine the striatal gene expression of dopamine signaling molecules, the striatal compartment organization, and the neural connections to and from the striatum at different developmental stages in Aim1. In Aim 2 and Aim 3, we propose to take advantage of the genetic tools to either eliminate or re-express MeCP2 specifically in the striatum, and characterize these conditional mice with the same set of molecular, cellular and behavioral assays. Our goal is to assess the role of MeCP2 in the development of the striatum and the role of the striatum in the onset of RTT psychomotor symptoms. It is our hope that this proposed study will not only provide a neural basis for the understanding of psychomotor abnormalities in RTT, but also identify a behaviorally relevant brain region and neurotransmission systems, as well as a developmentally early time window to medicate the psychomotor symptoms in RTT. |
