MICA: Correction of behavioural, circuit and cellular deficits in rat models of ID/ASD

智力残疾(ID)和自闭症谱系障碍(ASD)是共同发生的疾病，大约在1-2岁时首次诊断出来。它们影响了大约2%-3%的人口，仅在英国就有100万-200万人患有ID/ASD。然而，这些疾病的治疗方法往往侧重于通过特殊教育或药物治疗来管理症状，针对焦虑和癫痫等特定症状。迫切需要开发更有效的治疗方法来逆转和/或预防这些脑部疾病。两个研究领域已经为我们设想ID/ASD的潜在治疗方法提供了翻天覆地的变化。首先，尽管数百个基因与导致ID/ASD有关，但最近的证据表明，许多遗传原因可能与大脑发育有关，因此为一种基因开发的治疗方法可能对另一种基因有效。其次，虽然以前认为只有在症状首次出现的早期发育阶段才能有效治疗，但最近的证据表明，这些疾病的至少某些形式可能在一生中都是可以治疗的。ID/ASD最常见的两种遗传形式是脆性X综合征(FXS)和SynGAP单倍体功能不全。两者都是由单个基因的基因改变造成的，因此，在实验室进行研究相对简单。我们实验室之前的工作表明，这两种疾病可能在海马体中有共同的病理变化，海马体是大脑中负责许多形式学习和记忆的区域。使用这些疾病的新的大鼠模型，我们建议扩展这些研究，看看它们是否也在大脑中控制情绪和焦虑的区域，即杏仁核和前额叶皮质中看到类似的变化。我们还将测试是否可以防止在发育过程中出现任何改变，并且一旦出现与ID/ASD相关的症状，是否可以在老年动物身上挽救这些改变。我们将测试目前正在开发的三种令人兴奋的治疗FXS的新药干预措施。每一种干预措施都将被测试其挽救脑细胞变化、脑细胞之间连接的能力，以及这些大脑发育变化导致的行为后果。

Intellectual disabilities (IDs) and autism spectrum disorders (ASDs) are co-occurring disorders that are first diagnosed at about 1-2 years of age. They affect approximately 2-3% of the population, between 1-2 million people in the UK alone have an ID/ASD. However, therapeutic approaches for these disorders tend to focus on managing symptoms using special education or medications that target specific symptoms such as anxiety and seizure. There is an urgent need to develop more effective treatments to reverse and/or prevent these brain disorders.Two areas of research have provided a sea change in how we envision potential treatments for ID/ASD. First, despite the fact that hundreds of genes have been implicated in causing ID/ASD, recent evidence suggests many genetic cause may share changes in brain development and hence treatment developed for one, may be effective for another. Second, while it was previously thought that there treatment would only be effective during early development when symptoms first appear, recent evidence suggests that at least some forms of these disorders may be treatable throughout the lifespan. Two of the most common genetic forms of ID/ASD are Fragile X Syndrome (FXS) and SYNGAP haploinsufficiency. Both result from genetic alteration of a single gene and hence, are relatively straightforward to study in the laboratory. Previous work from our laboratories indicates that these two disorders may share a common pathology in the hippocampus, the region of the brain responsible for many forms of learning and memory. Using novel rat models of these disorders, we propose to extend these studies to see whether they we also see similar changes in the regions of the brain that control emotion and anxiety, namely the amygdala and prefrontal cortex. We will also test whether any alterations can be prevented from emerging during development and can be rescued in older animals, once ID/ASD related symptoms have emerged. We will test three exciting new drug interventions that are currently being developed for treatment of FXS. Each intervention will be tested for their ability to rescue changes in brain cells, in the connections between brain cells, as well as the behavioural consequences that result from these alterations in brain development.