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）是一组异质性神经发育障碍，其特征在于三个行为缺陷领域：社会互动受损、语言发育延迟和运动刻板。虽然自闭症的异质性临床表现的病因尚不清楚，但一种假设是ASD是神经发育缺陷的结果，这些缺陷针对介导ASD中受影响的行为的特定神经回路/网络。 我们的初步研究的小鼠模型，进行了CNS特异性缺陷的纹状体黑质中棘神经元（MSN）富集的转录因子，Zfp 521（Zfp 521 cko）显示出生后的发展开始的运动刻板行为类似的运动刻板与ASD。Zfp 521 cko小鼠表现出的运动刻板行为，包括用前肢梳理面部/头部、舔身体、一只后肢的快速拍打和快速头部抽搐，是非常频繁的、使人衰弱的，引起自我伤害性病变，并损害行为学上的正常行为，即筑巢。 基于这些令人信服的初步研究，我们假设Zfp 521在纹状体黑质MSNs中协调了一个关键的转录程序，这对它们的正常成熟至关重要，并且这种分子程序的破坏可能导致运动刻板症。为此，我们提出的研究将集中在以下目的：（1）通过在纹状体黑质MSNs或纹状体苍白MSNs中选择性转基因表达Zfp 521来遗传拯救运动刻板症和纹状体回路功能障碍;和（2）使用FACS阵列技术在Zfp 521 cko、D1-BAC-Zfp 521转基因小鼠和野生型小鼠中纯化的纹状体黑质MSNs的发育表达谱。后一项研究可能有助于确定运动刻板症发生之前和之后纹黑质MSN中Zfp 521的关键下游转录靶点。 我们提出的研究是非常重要的，因为它可能提供新的电路和分子的见解，运动刻板症的神经发育基础，在自闭症的关键领域受到影响。此外，在研究中获得的分子见解可能是进一步研究ASD运动刻板症的遗传病因学和开发新的治疗方法以改善ASD和其他神经精神疾病中的行为缺陷的基础。 公共卫生相关性：运动刻板是自闭症谱系障碍（ASD）行为障碍的核心领域。我们的研究将探讨新的基底神经节电路和分子机制的神经发育发病的运动刻板症使用小鼠遗传模型。我们的研究将确定选择性纹状体黑质神经元功能障碍是否可能是运动刻板症的原因，并将确定基底神经节电路特异性候选基因和分子通路，这可能是我们模型中运动刻板症的基础。我们的研究可能提供新的分子和电路水平的神经生物学见解的发病机制和治疗的运动刻板的ASD和相关的神经精神疾病。

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.