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

MICA：纠正 ID/ASD 大鼠模型的行为、回路和细胞缺陷

• 批准号: MR/P006213/1
• 负责人: Peter Kind
• 金额: $ 139.6万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP006213%2F1
• 关键词: MICA; Correction; behavioural; circuit; cellular

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.

智力残疾（ID）和自闭症谱系障碍（ASD）是在大约1-2岁时首次诊断的共同发生的疾病。他们影响大约2-3%的人口，仅在英国就有1-2百万人患有ID/ASD。然而，这些疾病的治疗方法往往侧重于使用针对特定症状（如焦虑和癫痫发作）的特殊教育或药物来管理症状。迫切需要开发更有效的治疗方法来逆转和/或预防这些大脑疾病。两个研究领域为我们如何设想ID/ASD的潜在治疗方法提供了巨大的变化。首先，尽管有数百个基因与导致ID/ASD有关，但最近的证据表明，许多遗传原因可能会在大脑发育中发生变化，因此为一种疾病开发的治疗方法可能对另一种疾病有效。其次，虽然以前人们认为治疗只有在症状首次出现的早期发育期间才有效，但最近的证据表明，至少某些形式的这些疾病可能在整个生命周期中都可以治疗。ID/ASD的两种最常见的遗传形式是脆性X综合征（FXS）和SYNGAP单倍不足。两者都是由单个基因的遗传改变引起的，因此在实验室中进行研究相对简单。我们实验室以前的工作表明，这两种疾病可能在海马体中有共同的病理学，海马体是大脑中负责多种形式学习和记忆的区域。使用这些疾病的新大鼠模型，我们建议扩展这些研究，看看我们是否也看到控制情绪和焦虑的大脑区域，即杏仁核和前额皮质的类似变化。我们还将测试在发育过程中是否可以防止出现任何改变，并且一旦出现ID/ASD相关症状，是否可以在老年动物中进行挽救。我们将测试三种目前正在开发的用于治疗FXS的令人兴奋的新药干预措施。每种干预措施都将被测试其拯救脑细胞变化的能力，脑细胞之间的连接，以及大脑发育中这些变化所导致的行为后果。

项目成果

Altered dendritic spine function and integration in a mouse model of Fragile X Syndrome

脆性 X 综合征小鼠模型中树突棘功能和整合的改变

• DOI: 10.1101/396986
• 发表时间: 2018
• 作者: Booker S

Additional file 2 of Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3-/y rat model of autism

Nlgn3-/y 自闭症大鼠模型中飞行冻结反应不平衡及其细胞相关性的附加文件 2

• DOI: 10.6084/m9.figshare.20336962
• 发表时间: 2022
• 作者: Anstey N

Developmental trajectory of episodic-like memory in rats.

• DOI: 10.3389/fnbeh.2022.969871
• 发表时间: 2022
• 期刊: Frontiers in behavioral neuroscience
• 影响因子: 3
• 作者: Asiminas A;Lyon SA;Langston RF;Wood ER
• 通讯作者: Wood ER

Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.

• DOI: 10.1126/scitranslmed.aao0498
• 发表时间: 2019-05-29
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Asiminas A;Jackson AD;Louros SR;Till SM;Spano T;Dando O;Bear MF;Chattarji S;Hardingham GE;Osterweil EK;Wyllie DJA;Wood ER;Kind PC
• 通讯作者: Kind PC

Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome.

• DOI: 10.1186/s13229-022-00528-z
• 发表时间: 2022-12-20
• 期刊: Molecular autism
• 影响因子: 6.2