Identifying Convergent Circuit Disruptions Across Genetically-Distinct Models of Autism

在遗传上不同的ASD大鼠模型中识别会聚电路中断 摘要：人类遗传学和动物研究的最新进展极大地提高了我们的 了解自闭症谱系障碍（ASD）的分子和细胞基础。将这些风险 自闭症临床症状的因素仍然是一个重大挑战，阻碍了自闭症的发展。 ASD治疗，最近的大规模临床试验结果令人失望。一项基本 问题是，不同的ASD突变是否在神经元的某些水平上汇聚在共同的疾病机制上。 最终导致自闭症的行为和神经认知表型。识别 这些病理生理学汇合点对于发展治疗策略是必要的， 在遗传异质性ASD中进行推广。我们之前已经证明， 自闭症的两个最常见的遗传学定义的原因-脆性X综合征的Fmr 1 KO小鼠模型 (FX)结节硬化复合体（TSC）的Tsc 2 +/-小鼠模型-表现出相反的突触和细胞突触， 表型对相反的药物干预反应，尽管共享分子途径 并表现出相似的行为表型。该提案将确定Fmr 1和Tsc 2突变是否 集中在共同的电路中断，可以解释这些疾病的共同行为表型。 我们将通过听觉系统的透镜来解决这个问题，因为听觉处理障碍是 ASD中一种常见的使人衰弱的感觉表型，直接影响沟通和社会行为 同时还提供稳健的和预防相关的行为和生理读出，由于其良好的- 具有神经解剖学和进化保守性的特点。具体而言，该提案将测试 假设由于兴奋性/抑制性突触平衡改变和失调引起回路过度兴奋 表达小清蛋白（PV+）的中间神经元功能是一种会聚性疾病机制， FX和TSC大鼠模型中听觉感知和信息处理的缺陷。这将是 通过将大鼠模型的独特行为学与体内和离体相结合来实现 电生理记录、细胞类型特异性光遗传学操作和分子谱分析 技术.确定Fmr 1和Tsc 2突变如何导致听觉处理缺陷和神经回路 功能障碍不仅有助于确定新的治疗方法，使这些疾病的感觉表型， 可能揭示反复出现的病理生理学基序，这些基序概括了神经认知领域， 扩展到各种形式的ASD。

Identifying Convergent Circuit Disruptions Across Genetically-Distinct Rat Models of ASD Summary: Recent advances from human genetic and animal studies have greatly increased our understanding of the molecular and cellular basis of autism spectrum disorders (ASD). Connecting these risk factors to clinical symptoms in autism remains a significant challenge that has impeded the development of ASD therapies, as evidenced by disappointing results from recent large-scale clinical trials. A fundamental question is if distinct ASD mutations converge on shared disease mechanisms at some level of neuronal function to ultimately give rise to the behavioral and neurocognitive phenotypes that define autism. Identifying these pathophysiological convergence points is essential for developing treatment strategies that may generalize across genetically heterogenous forms of ASD. We have previously shown that rodent models of the two most common genetically-defined causes of autism— Fmr1 KO mouse model of Fragile X syndrome (FX) and Tsc2+/- mouse model of tuber sclerosis complex (TSC)— exhibit opposite synaptic and cellular phenotypes that responded to opposite pharmacological interventions, despite sharing a molecular pathway and presenting with similar behavioral phenotypes. This proposal will determine if Fmr1 and Tsc2 mutations converge on common circuit disruptions that can account for shared behavioral phenotypes in these disorders. We will address this question through the lens of the auditory system, as auditory processing impairments are a common and debilitating sensory phenotype in ASD that directly impacts communicative and social behavior while also providing robust and translationally-relevant behavioral and physiological read-outs, due to its well- characterized neuroanatomy and evolutionary conserved nature. Specifically, this proposal will test the hypothesis that circuit hyperexcitability due to altered excitatory/inhibitory synaptic balance and dysregulated parvalbumin expressing (PV+) interneuron function is a convergent disease mechanism that leads to shared deficits in auditory perception and information processing in rat models of FX and TSC. This will be accomplished by combining the unique behavioral advantaged of rat models with in vivo and ex vivo electrophysiological recordings, cell-type specific optogenetic manipulations, and molecular profiling techniques. Determining how Fmr1 and Tsc2 mutations lead to auditory processing deficits and neural circuit dysfunction will not only help identify novel therapies for disabling sensory phenotypes in these disorders, but may shed light on recurring pathophysiological motifs that generalize across neurocognitive domains and extend to diverse forms of ASD.