Spine development and activity-dependent plasticity in the hippocampus of a mouse model of the Fragile X Syndrome

脆性 X 综合征小鼠模型海马的脊柱发育和活动依赖性可塑性

• 批准号: 244181329
• 负责人: Professor Dr. Martin Korte
• 金额: --
• 依托单位: Zoologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/244181329?language=en
• 关键词: Spine; development; activity; dependent; plasticity

The Fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism. Patients with FXS can show attention deficits and autism spectrum disorder (ASD) symptoms like stereotypic behavior and excessive adherence to patterns which can be associated with perturbed hippocampal networks. The hippocampus is indeed crucially involved in pattern separation/ completion during memory formation. In this respect the CA3 region is of special interest because of the auto-associative nature of the recurrent inputs. Unlike most other cells in the cortex, these cells actually are connected to a high degree to themselves. In contrast to this, the exceptionally strong and sparse mossy fiber input onto CA3 neurons is described as a ‘detonator’ synapse, directing plasticity and the information processing in the recurrent network.A hallmark of FXS is an immature spine profile which can be found in patients as well as in the FXS mouse model (fmr1 KO). We could recently uncover a novel role of FMRP in restricting synapse development of mossy fiber inputs as the postsynaptic thorny excrescences (TEs) on CA3 neurons are premature during development in fmr1 KO mice. In contrast to this, analysis of the recurrent inputs displayed the well documented immature spine. Our preliminary data provide therefore evidence for a strong dysregulation of synapse maturation in a synapse-type specific manner in the CA3 subregion. Most likely associated with a detrimental outcome for information processing in CA3 neurons and for hippocampal function as a whole.In our current project we would like to determine the precise development of these synaptic phenotypes and to what extent they persist into adulthood both under normal laboratory conditions and in an enriched environment as a potential treatment for FXS. We will use general hippocampus-dependent and specifically CA3-dependent learning paradigms to study the behavioral outcome of synaptic alterations in CA3 neurons in juvenile and adult mice. High-resolution imaging and electrophysiological techniques will allow us to combine knowledge about structure and function of the respective synapse type under naïve conditions as well as following rearing in an enriched environment or memory training at different stages during development to reveal the underlying cellular mechanisms for behavioral impairments. Our experiments will help to understand the structure-function-relationship and the role for behavioral outcome of two important synapses in the mouse hippocampus and how this is altered in an FXS mouse model. In order to understand the role of the CA3 region for FXS it is important to combine knowledge about both synapses throughout development to understand how alterations in one or both synapse types affects information processing. This will not only contribute to a better understanding of the cellular mechanisms underlying FXS but also reveal details about hippocampal function in general.

脆性X综合征（FXS）是认知障碍和自闭症的主要单基因原因。FXS患者可能表现出注意力缺陷和自闭症谱系障碍（ASD）症状，如刻板行为和过度坚持模式，这可能与海马网络紊乱有关。海马体确实在记忆形成过程中对模式分离/完成起着至关重要的作用。在这方面，CA 3区域是特别感兴趣的，因为经常性输入的自联想性质。与大脑皮层中的大多数其他细胞不同，这些细胞实际上与它们自己有着高度的联系。与此相反，输入到CA 3神经元上的异常强大和稀疏的苔藓纤维被描述为“引爆器”突触，指导可塑性和递归网络中的信息处理。FXS的一个标志是不成熟的脊柱轮廓，可以在患者和FXS小鼠模型（fmr 1 KO）中发现。我们最近发现FMRP在限制苔藓纤维输入的突触发育中的新作用，因为在fmr 1 KO小鼠的发育过程中，CA 3神经元上的突触后多刺赘生物（TEs）是早熟的。与此相反，对反复输入的分析显示了有据可查的不成熟脊柱。因此，我们的初步数据提供了证据，在CA 3亚区的突触类型特异性的方式突触成熟的强烈失调。最有可能与CA 3神经元信息处理和海马功能的有害结果相关，在我们目前的项目中，我们想确定这些突触表型的精确发育，以及在正常实验室条件下和丰富的环境中，它们在多大程度上持续到成年，作为FXS的潜在治疗方法。我们将使用一般的海马依赖性，特别是CA 3依赖性的学习范式来研究幼年和成年小鼠CA 3神经元突触改变的行为结果。高分辨率成像和电生理技术将使我们能够将联合收割机在幼稚条件下以及在丰富环境中饲养或在发育过程中的不同阶段进行记忆训练后有关相应突触类型的结构和功能的知识结合起来，以揭示行为障碍的潜在细胞机制。我们的实验将有助于了解结构-功能-关系和行为结果的作用，在小鼠海马中的两个重要的突触，以及如何在FXS小鼠模型中改变。为了理解CA 3区在FXS中的作用，重要的是联合收割机结合整个发育过程中关于两种突触的知识，以理解一种或两种突触类型的改变如何影响信息处理。这不仅有助于更好地理解FXS的细胞机制，而且还揭示了海马功能的一般细节。