Characterization and reversibility of cognitive deficits in a mouse model of Tatton-Brown-Rahman syndrome.

塔顿-布朗-拉赫曼综合征（TBRS）是最近发现的一种罕见的遗传性神经发育障碍，其特征是身材高大，面部外观独特，智力残疾。TBRS是由DNMT3A基因的突变引起的变异引起的。TBRS无法治愈，治疗的目标是改善症状。最近，几项神经发育疾病动物模型的研究表明，在发育后期更换功能失调基因或靶向基因相关信号可以逆转成年小鼠的认知缺陷。研究进一步表明，与这些疾病相关的基因在一生中都是学习和记忆所必需的。因此，这表明在这种情况下，成熟大脑中的基因替换至少可以恢复一些疾病表型，例如认知能力。我们已发表和未发表的研究结果表明，Dnmt3a编码酶Dnmt3a1和Dnmt3a2在成人海马记忆形成中的作用。因此，可以想象，恢复成年TBRS小鼠的Dnmt3a功能可以改善认知缺陷。这一假设将在当前的提案中得到解决。这将通过两个主要的研究方向来实现。首先，我们将在最近开发的TBRS小鼠模型中发现迄今为止未知的脑和神经元功能改变。我们将描述不同发育阶段的大脑和形态特征，并分析Dnmt3aKO/+小鼠在一系列记忆测试中的表现。此外，我们将研究与记忆形成和检索相关的神经元转录反应和激活模式是否在这些小鼠中受到影响，如果受到影响，它们是否与学习缺陷相关。其次，我们将在同一模型中解决认知缺陷和相关细胞功能障碍的可逆性潜力。我们将关注已识别的分子、细胞和行为缺陷，并评估成年期基因替换是否能恢复这些功能障碍。总的来说，这项研究计划旨在扩展我们迄今为止对TBRS中智力残疾的机制原因的非常有限的理解。这将有助于了解tbrs样表型是否在发育过程中被不可逆地决定，或者是否至少可以通过基因靶向成熟神经元来挽救学习和记忆缺陷。这些发现将为开发治疗和干预措施铺平道路。

Tatton-Brown-Rahman syndrome (TBRS) is a recently described rare genetic neurodevelopmental disorder characterized by tall stature, a distinctive facial appearance, and intellectual disability. TBRS is caused by variants in the DNMT3A gene that arise from de novo mutations in the gene. There is no cure for TBRS and treatments are targeted at ameliorating symptoms. Recently, several studies of animal models of neurodevelopmental diseases showed that replacing the dysfunctional gene or targeting gene-related signaling at later developmental stages reversed cognitive deficits in adult mice. It was further demonstrated that the genes associated with these disorders are continuously required for learning and memory throughout life. Hence, indicating that in such cases gene replacement in the mature brain restores at least some disease phenotypes, such as cognitive abilities. Our published and unpublished findings demonstrated a role for the Dnmt3a encoded enzymes, Dnmt3a1 and Dnmt3a2, in the adult hippocampus in memory formation. Therefore, it is conceivable that restoring Dnmt3a function in TBRS mice in adulthood ameliorates cognitive deficits. This hypothesis will be addressed in the current proposal. This will be achieved by taking two main research directions. First, we will uncover the so far unknown alterations in brain and neuronal function in a recently developed mouse model of TBRS. We will characterize brain and morphological features at distinct developmental stages and analyze the performance of Dnmt3aKO/+ mice in a battery of memory tests. Moreover, we will investigate whether neuronal transcriptional responses and activation patterns, relevant for memory formation and retrieval, are affected in these mice and if so, whether they correlate with learning deficits. Second, we will address the reversibility potential of cognitive deficits and associated cellular dysfunctions in the same model. We will focus on the identified molecular, cellular, and behavioral deficits and assess whether gene replacement in adulthood restores these dysfunctions. Overall, this research program is primed to expand our so far very limited understanding of the mechanistic causes of intellectual disability in TBRS. It will provide insight into whether TBRS-like phenotypes are irreversibly determined during development or if at least learning and memory deficits are rescuable upon gene targeting of mature neurons. These findings will pave the way to the development of treatments and interventions.