A novel neural circuit analysis paradigm to model autism in mice

描述(申请人提供)：一种新的自闭症小鼠模型的神经电路分析范式自闭症谱系障碍(ASD)的行为障碍背后的电路缺陷仍然知之甚少。这一知识对于开发有效的治疗方法至关重要。人类ASD的相当大的分子异质性和人类研究的明显局限性使具有与人类相同的靶向突变的突变小鼠获得了一个独特的机会，因为它允许在分子和电路水平上进行操作。越来越多的ASD模型同时具有“结构”(分子缺陷模仿人类ASD)和“Face”(相当于人类ASD核心特征的行为损害)的有效性。目前在突变小鼠中建立人类ASD模型的分析范式侧重于使用切片生理学和行为分析来分析突触的发育和功能。这些研究提供了支持ASD模型中突触功能障碍的一般结论的证据。然而，这些发现几乎没有提供对行为障碍背后的电路机制的洞察，因为研究选定大脑区域的突触的发现经常是不同的，并且在不同的研究中不一致。自闭症研究的根本挑战在于理解基因功能变化如何扰乱负责自闭症行为背后正常功能过程的大规模大脑网络的复杂性。由于这些原因，在转基因突变小鼠中模拟人类ASD的领域需要一种新的分析范式来剖析电路或网络水平的功能障碍。我们开发了一种新的多单位活体编码技术，可以同时从自由运动动物的多达11个脑区获得神经活动。这种新技术为检测功能失调的神经电路和网络提供了一种可行的方法。我们还培育并鉴定了独特的SHANK2外显子24(Shank3e24)和Shank3外显子4-22(Shank3e4-22)缺失突变小鼠，它们对人类ASD具有很强的结构和表面有效性。这些突变的小鼠提供了独特的机会来开发一种新的分析范式来解剖电路功能障碍。该项目的长期目标是使用ASD小鼠模型来确定ASD行为背后的功能障碍电路。中心假设是，在Shank3e4-22和Shank2e24突变小鼠中，将观察到不同相关神经回路的功能障碍同步。具体目标是使用我们团队开创的一种新的体内多单位记录技术来识别这些突变小鼠中潜在的社会缺陷和重复行为的功能障碍的神经回路。这些实验将导致识别内表型的电生理生物标记物，这将有助于验证新的神经精神药物的新分子靶点，增强当前用于ASD的神经调节疗法的靶向性，并促进闭合环神经调节性“起搏器”的开发，后者直接修复ASD行为表现背后的功能障碍的大脑回路。这些发现将解决我们知识中的一个重大差距，并提供证据支持使用突变小鼠模拟人类ASD的范式转变。

DESCRIPTION (provided by applicant): A Novel Neural Circuit Analysis Paradigm to Model Autism in Mice The circuit defects underlying the behavioral impairments of autism spectrum disorders (ASD) remains poorly understood. This knowledge is critical for development of effective treatments. The considerable molecular heterogeneity in human ASD and the apparent limitations in human studies renders mutant mice with targeted mutations equivalent to humans a unique opportunity because it allows manipulation at both molecular and circuit levels. There is an increasing list of ASD models with both "construct" (molecular defect mimics human ASD) and "face" (behavioral impairments equivalent to core feature of human ASD) validity. The current analytic paradigm of modeling human ASD in mutant mice focuses on analyzing synaptic development and function using slice physiology and behavior analysis. These studies have produced evidence supporting a general conclusion of synaptic dysfunction in ASD models. However, these findings offer little insight into the circuit mechanism underlying behavioral impairments because the findings from studying the synapses in select brain regions are frequently variable and inconsistent among different studies. The fundamental challenge of ASD research lies within the complexity of understanding how alterations in gene function disrupt large scale brain networks responsible for normal functional process underlying autistic behaviors. For these reasons, the field of modeling human ASD in genetically modified mutant mice demands a new analytic paradigm to dissect the dysfunction at circuit or network levels. We have developed a novel multi-unit in vivo recoding technique that can acquire neural activity from as many as 11 brain regions in free moving animals simultaneously. This novel technique offers a feasibility to detect dysfunctional neural circuit and network. We have also produced and characterized unique Shank2 exon 24 (Shank3e24) and Shank3 exon 4-22 (Shank3e4- 22) deletion mutant mice that have strong construct and face validity for human ASD. These mutant mice provide unique opportunities to develop a novel analytic paradigm for dissecting circuit dysfunction. The long term goal of this project is to define dysfunctional circuit underlying ASD behaviors using ASD mouse models. The central hypothesis is dysfunction synchrony across distinct relevant neural circuits will be observed in Shank3e4-22 and Shank2e24 mutant mice. The specific objective is to identify the dysfunctional neural circuits underlying social deficits nd repetitive behaviors in these mutant mice using a novel in vivo multiple-unit recording technique pioneered by our team. These experiments will lead to the identification of electrophysiological biomarkers of endophenotypes that will aid in the validation of novel molecular targets for novel neuropsychiatric drugs, enhance the targeting of current neuromodulatory therapies for use in ASD and facilitate the development of closed loop neuromodulatory "pacemakers" which directly repair the dysfunctional brain circuits underlying the behavioral manifestations in ASD. These findings will address a significant gap in our knowledge and provide evidence to support a paradigm shift in modeling human ASD using mutant mice.