Basal Ganglia Circuitry and Molecules in Pathogenesis of Motor Stereotypy

描述（由申请人提供）：自闭症谱系障碍（asd）是一种异质性的神经发育障碍，其特征是三个行为缺陷领域：社交障碍、语言发展迟缓和运动刻板印象。尽管自闭症异质性临床表现背后的病因尚不清楚，但有一种假设认为，自闭症是针对特定神经回路/网络的神经发育缺陷的结果，这些神经回路/网络介导了自闭症中受影响的行为。我们对一个携带cns特异性纹状体中棘神经元（MSN）富集转录因子Zfp521 （Zfp521cko）缺陷的小鼠模型进行了初步研究，结果显示，出生后发育的运动刻板行为类似于与asd相关的运动刻板行为。Zfp521cko小鼠表现出的运动刻板印象，包括用前肢梳理面部/头部、舔身体、快速拍打一只后肢和快速头部抽搐，是非常频繁的，使人虚弱，导致自残损伤，并损害行为学上正常的行为，即筑巢。基于这些引人注目的初步研究，我们假设Zfp521在纹状核msn中编排了一个关键的转录程序，这对它们的正常成熟至关重要，并且该分子程序的破坏可能导致运动刻板印象。为此，我们拟开展的研究将集中在以下几个方面：(1)通过在纹状核或纹状顶核中选择性表达Zfp521基因，从基因上拯救运动刻板印象和纹状体回路功能障碍；(2)利用facs阵列技术分析纯化的纹状核MSNs在Zfp521cko、D1-BAC-Zfp521转基因小鼠和野生型小鼠中的发育表达谱。后一项研究可能有助于确定Zfp521在运动刻板印象发生之前和之后的纹状核msn中的关键下游转录靶点。我们提出的研究具有重要意义，因为它可能为运动刻板印象的神经发育基础提供新的电路和分子见解，运动刻板印象是asd中受影响的一个关键领域。此外，该研究获得的分子见解可能为进一步研究asd运动刻板印象的遗传病因以及开发新的治疗方法来改善asd和其他神经精神疾病的这种行为缺陷奠定基础。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders characterized by three domains of behavioral deficits: impaired social interaction, delayed language development, and motor stereotypy. Although etiologies underlying the heterogeneous clinical manifestations of autism remain unclear, one hypothesis is that ASDs are the result of neurodevelopmental deficits targeting the specific neural circuits/networks that mediate the behaviors affected in ASDs. Our preliminary studies of a mouse model that carries a CNS-specific deficiency of the striatonigral medium spiny neuron (MSN)-enriched transcription factor, Zfp521 (Zfp521cko) show postnatal developmental onset of motor stereotypic behaviors resembling the motor stereotypies associated with ASDs. The motor stereotypies exhibited by the Zfp521cko mice, which include facial/head grooming with the forelimbs, body licking, rapid flapping of one hindlimb, and rapid head twitches, are highly frequent, debilitating, cause self-injurious lesions, and impair an ethologically normal behavior, nest building. Based on these compelling preliminary studies, we hypothesize that Zfp521 orchestrates a critical transcriptional program within the striatonigral MSNs which is crucial for their normal maturation, and that disruption of this molecular program can result in motor stereotypies. To this end, our proposed studies will focus on the following Aims: (1) Genetic rescue of the motor stereotypies and striatal circuitry dysfunction by selective transgenic expression of Zfp521 in striatonigral MSNs or striatopallidal MSNs; and (2) Developmental expression profiling of purified striatonigral MSNs in Zfp521cko, D1-BAC-Zfp521 transgenic mice and wildtype mice using the FACS-array technology. The latter study may help to identify the critical downstream transcriptional targets of Zfp521 in the striatonigral MSNs prior to and after the onset of motor stereotypies. Our proposed study is highly significant since it may provide novel circuitry and molecular insights into the neurodevelopmental basis of motor stereotypy, a critical domain affected in ASDs. Furthermore, the molecular insights gained in the study may be a basis to further study the genetic etiology of motor stereotypy in ASDs and to develop novel therapeutics to ameliorate such behavioral deficits in ASDs and other neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: Motor stereotypy is a core domain of behavioral impairment in Autism Spectrum Disorders (ASDs). Our study will investigate novel basal ganglia circuitry and molecular mechanisms underlying the neurodevelopmental onset of motor stereotypy using a mouse genetic model. Our study will establish whether selective striatonigral neuron dysfunction may be the cause of motor stereotypy and will identify basal ganglia circuitry specific candidate genes and molecular pathways which may underlie the motor stereotypy in our model. Our study may provide novel molecular and circuitry level neurobiological insights into the pathogenesis and treatment of motor stereotypy in ASDs and related neuropsychiatric disorders.