Identifying Convergent Circuit Disruptions Across Genetically-Distinct Models of Autism

在遗传不同的ASD大鼠模型中识别汇聚性电路中断 摘要：人类基因和动物研究的最新进展大大增加了我们的 了解自闭症谱系障碍(ASD)的分子和细胞基础。将这些风险联系起来 自闭症临床症状的因素仍然是阻碍自闭症发展的重大挑战 ASD疗法，最近大规模临床试验令人失望的结果证明了这一点。一项基本原则 问题是，不同的ASD突变是否在某些神经元水平上汇聚在共同的疾病机制上 最终导致定义自闭症的行为和神经认知表型。识别 这些病理生理汇聚点对于制定治疗策略至关重要，这些治疗策略可能 在遗传上不同的ASD形式中推广。我们之前已经证明了啮齿动物模型 自闭症的两个最常见的基因定义原因--脆性X综合征的Fmr1 KO小鼠模型 结节硬化症(TSC)模型(FX)和TSC2+/-小鼠模型--呈现相反的突触和细胞 对相反的药物干预有反应的表型，尽管有相同的分子途径 并且表现出相似的行为表型。这项提议将确定Fmr1和TSC2突变 集中在常见的电路中断上，这些中断可以解释这些疾病中共同的行为表型。 我们将通过听觉系统的透镜来解决这个问题，就像听觉处理障碍 ASD中一种常见的、使人衰弱的感觉表型，直接影响交流和社交行为 同时还提供健壮且与翻译相关的行为和生理读出，由于其良好的 以神经解剖学和进化保守性为特点。具体地说，这项提案将考验 兴奋性/抑制性突触平衡改变和调节失调所致的电路过度兴奋性假说 小白蛋白表达(PV+)中间神经元功能是一种导致共享的聚集性疾病机制 FX和TSC模型大鼠的听觉和信息加工缺陷。这将是 通过将大鼠模型独特的行为优势与体内和体外相结合来实现 电生理记录、特定细胞类型的光遗传操作和分子图谱 技巧。确定Fmr1和TSC2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使这些障碍的感觉表型失效的新疗法，而且 可能有助于揭示反复出现的跨神经认知领域的病理生理学主题 扩展到各种形式的自闭症。

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.