Validating Electrophysiological Endophenotypes as Tranlational Biomarkers of Auti

描述（由申请人提供）：语言障碍是自闭症谱系障碍（ASD）的主要特征，会导致严重的残疾。尽管如此，针对沟通问题的可行治疗方法很少，而且人们对遗传和环境因素如何导致这一核心缺陷的发展仍然知之甚少。目前的自闭症啮齿动物模型经常忽略交流异常，因此无法研究自闭症谱系障碍的全部核心症状。因此，开发ASD动物模型中沟通缺陷的预测方法，探索语言障碍的潜在机制和潜在治疗方法至关重要。本提案的目的是开发和验证自闭症小鼠模型中原始语言功能的电生理和行为测量。我们在费城儿童医院的合作者在临床研究中使用脑磁图建立了一套自闭症儿童接受性语言功能受损的电生理生物标志物。本研究旨在将这些听觉诱发电位（AEP）受损的临床发现转化为评估自闭症小鼠模型的原始语言功能。拟议的研究将调查在产前接受致畸剂丙戊酸治疗的小鼠的AEP变化，丙戊酸是一种已建立的自闭症样行为啮齿动物模型。目标将包括延迟的AEP潜伏期，改变的错配负性，以及伽马振荡缺陷，这些已经在自闭症受试者的临床研究中被确立为语言障碍的电生理生物标志物。第二个目的是通过评估新生儿和成年超声发声（usv），用行为测量来评估这些小鼠的交流功能。将评估行为和电生理测量之间的相关性，以加强这些方法的有效性。这些研究的完成将进一步开发新的方法来评估小鼠的接受性和表达性交流，从而为开发新的自闭症治疗方法提供更完整的临床前范例。

DESCRIPTION (provided by applicant): Language impairment is a cardinal feature of Autism Spectrum Disorders (ASD) that causes significant disability. Despite this, few viable treatments target communication problems and there remains a poor understanding of how genetic and environmental factors contribute to the development of this core deficit. Current rodent models of autism frequently ignore communicative abnormalities, and thus fail to investigate the full spectrum of core symptoms in ASD. Therefore, the need to develop predictive measures of communication deficits in animal models of ASD which explore underlying mechanisms and potential treatments for language impairment is of paramount importance. The goal of this proposal is to develop and validate electrophysiological and behavioral measures of proto-language functioning in a mouse model of autism. Clinical studies from our collaborators at Children's Hospital of Philadelphia have established a set of electrophysiological biomarkers of impaired receptive language functioning in autistic children using magnetoencephalography. This proposal seeks to translate these clinical findings of impaired auditory-evoked potentials (AEP) to assess proto-language functioning in a mouse model of autism. Proposed studies will investigate AEP changes in mice treated prenatally with the teratogen valproic acid, an established rodent model of autism-like behaviors. Targets will include delayed AEP latencies, altered mismatch negativity, and deficits in gamma oscillations, which have been established as electrophysiological biomarkers of language impairment in clinical studies of autistic subjects. The second aim is to assess communicative functioning in these mice with behavioral measures, by assessing newborn and adult ultrasonic vocalizations (USVs). Correlations between behavioral and electrophysiological measures will be assessed to strengthen the validity of these methods. Completion of these studies will further the development of novel methods to assess receptive and expressive communication in mice, thus providing a more complete preclinical paradigm in which to develop new therapeutic treatments for autism. PUBLIC HEALTH RELEVANCE: This project seeks to develop new ways to assess expressive and receptive communication in a mouse model of autism, using EEG techniques to measure electrical brain activity in a way analogous to methods currently used in clinical studies of autistic children. Completion of these studies will help further investigate how genetic and environmental insults can lead to language dysfunction, which is a core behavioral deficit in autism spectrum disorders (ASD). Ultimately, this work will further develop a more complete preclinical paradigm to help uncover underlying disease mechanisms and to develop new treatments for autism.