Physiological mechanisms underlying disrupted hippocampal function in Fragile X syndrome

项目概要/摘要。脆性X综合征（FX）是一种广泛存在的遗传性智力残疾。 目前缺乏针对FX潜在机制的有效治疗方法。外汇是最重要的单基因 自闭症谱系障碍的原因，因此许多个体与FX表现出异常的社会行为。 具有FX的个体也经常从事异常的空间行为，如“私奔”，游荡， 迷路了海马体是一种特别容易受到FX影响的大脑结构。很多证据表明 海马CA 2和CA 1区分别对社会行为和空间记忆很重要。然而， 很少有研究调查是否在社会和空间的神经生理机制的干扰 CA 2和CA 1的记忆功能是FX的社会行为和空间记忆障碍的基础。这 该项目的目标是通过调查亚细胞，细胞，电路， 啮齿类动物海马中社会和空间记忆操作的网络机制受损 FX模型这些研究将采用最先进的体内和体外电生理技术。体内 方法将被用来评估是否异常的细胞和网络机制与缺陷， 社会探索和空间记忆。体外实验将揭示改变的细胞机制 CA 2的内在特性和可塑性以及CA 1的异常抑制。两个物种的FX模型，特别是 将使用Fmr 1敲除（KO）大鼠和小鼠，以比较不同种属的FX病理生理学。 具体目标1将评估在探索社会刺激期间对CA 2神经元的输入强度是否 在Fmr 1 KO大鼠中比野生型大鼠更弱。该目标还将使用复杂的行为跟踪软件， 确定Fmr 1 KO大鼠在社会探索期间是否表现出异常的行为模式。具体目标2将 采用全细胞和膜片钳记录，包括直接从树突记录，在海马 切片以测试Fmr 1 KO大鼠和小鼠中的CA 2神经元是否显示受损的突触可塑性和反应 社会神经肽催产素。具体目标3将测试是否协调来自 CA 1神经元的集合被认为是空间记忆处理的重要网络机制， 在执行空间记忆任务的Fmr 1 KO大鼠中被破坏。协调整个合奏的扣球 海马神经元需要特定的CA 1中间神经元的适当定时激活。因此， FX中CA 1峰电位序列的协调可能反映了CA 1中间神经元的干扰。具体目标4将 采用特定类别的CA 1中间神经元和对CA 1锥体细胞的抑制性输入的全细胞记录 来检验抑制回路在FX中被破坏的假设。成功实现这些目标将为 关于FX中异常社会和空间行为的具体机制的新见解。获得了 对FX机制的深入了解有望为FX的干预提供新的靶点。

Project Summary/Abstract. Fragile X syndrome (FX) is a widespread type of inherited intellectual disability. Effective treatments that target mechanisms underlying FX are currently lacking. FX is the foremost monogenic cause of autism spectrum disorders, and thus many individuals with FX exhibit abnormal social behaviors. Individuals with FX also often engage in aberrant spatial behaviors such as “elopement”, wandering off and getting lost. The hippocampus is a brain structure that is particularly vulnerable to FX. Much evidence suggests that hippocampal areas CA2 and CA1 are important for social behaviors and spatial memory, respectively. Yet, few studies have investigated whether disturbances in neurophysiological mechanisms of social and spatial memory functions in CA2 and CA1 underlie social behavioral and spatial memory impairments in FX. This project’s goal is to address this gap in knowledge by investigating the extent to which subcellular, cellular, circuit, and network mechanisms of social and spatial memory operations in the hippocampus are impaired in rodent models of FX. The studies will employ state-of-the-art in vivo and in vitro electrophysiological techniques. In vivo approaches will be used to assess whether aberrant cellular and network mechanisms are related to deficits in social exploration and spatial memory. In vitro experiments will uncover cellular mechanisms underlying altered intrinsic properties and plasticity in CA2 and aberrant inhibition in CA1. Models of FX in two species, specifically Fmr1 knockout (KO) rats and mice, will be used, allowing comparison of FX pathophysiology across species. Specific Aim 1 will assess whether the strength of inputs to CA2 neurons during exploration of social stimuli is weaker in Fmr1 KO rats than wildtype rats. This Aim will also use sophisticated behavioral tracking software to determine whether Fmr1 KO rats show aberrant behavioral patterns during social exploration. Specific Aim 2 will employ whole cell and patch clamp recordings, including recordings directly from dendrites, in hippocampal slices to test whether CA2 neurons in Fmr1 KO rats and mice show impaired synaptic plasticity and responses to the social neuropeptide, oxytocin. Specific Aim 3 will test whether coordination of spike sequences from ensembles of CA1 neurons, believed to be an important network mechanism of spatial memory processing, is disrupted in Fmr1 KO rats performing spatial memory tasks. Coordination of spiking across ensembles of hippocampal neurons requires properly timed activation of specific CA1 interneurons. Thus, disrupted coordination of CA1 spike sequences in FX may reflect disturbances in CA1 interneurons. Specific Aim 4 will employ whole cell recordings of specific classes of CA1 interneurons and inhibitory inputs to CA1 pyramidal cells to test the hypothesis that inhibitory circuits are disrupted in FX. Successful completion of these Aims will provide novel insights about specific mechanisms underlying aberrant social and spatial behaviors in FX. Gaining a deeper understanding of FX mechanisms is expected to suggest novel targets for intervention in FX.