Defining Plasticity and Homeostasis in Fragile X Syndrome

项目摘要 我们建议在脆性X染色体小鼠模型中研究发育中杏仁核的回路稳态 综合征（FXS）-一种广泛性神经发育障碍（NDD），也是一种主要的单基因病因。 自闭症许多NDD，如FXS，其特征在于年龄依赖性症状发作和消退， 早年生活最近的证据，包括我们自己的出版物，从单基因小鼠模型的NDD揭示 突触可塑性的关键时期在开始、持续时间和偏移方面都有所改变。这改变了关键 NDD中的周期通常被称为“敏感时间窗口”-突触的时间调节窗口 损伤因此，敏感时间窗的识别对于理解大脑具有意义 发展，并可能表明脆弱时期时，治疗救援是最有效的。 我们已经确定了一个短暂的增强突触可塑性的时期，在发展中的杏仁核在Fmr1 FXS敲除（KO）小鼠模型（Vislay等人，JNeurosci 2013）。这类似于一个敏感的时间窗口 的可塑性。这一发现是建立在我们以前的观察基础上的，即抑制功能是显着的。 从出生后第21天（P）到成年年龄，Fmr 1科斯耗尽。我们提出了这样一个问题，"抑制 电路从出生就有缺陷，还是会发展成有缺陷的电路？”因此，我们检查了 在出生后发育的前三周，抑制回路功能的发展。在P10，当 GABAA受体介导的电流是抑制性的，Fmr 1科斯的抑制功能减弱。然而，在这方面， 令人惊讶地，我们观察到在P14 - 16之间存在缺陷抑制的稳态校正。这 抑制功能的增加仅仅是短暂的，因为这种校正最终不能由P21维持 时间点。到P21，突触抑制福尔斯下降到成年期正常功能以下（Olmos-Serrano 例如，JNeurosci 2010，Martin等人，JNeurophysiol 2014）。我们认为这种抑制功能的增加可能 是可塑性的“生物标志物”，因此代表了发育中的脆性X细胞的敏感时间窗。 杏仁核 在目前的建议中，我们将确定这种抑制的稳态波动是如何发生在Fmr 1科斯中的。 关键时间点。这些实验的共同目标是确定抑制功能的波动 影响电路功能、结构、可塑性和行为。在具体目标1中，我们将探讨这一现象 首先研究抑制回路是如何在 功能、连通性和解剖结构。在具体目标2中，我们将确定这一时期的稳态 影响出生后早期发育中的回路可塑性和特定行为。综上所述，我们的建议 实验将提供一个明确的识别电路的变化，改变突触的发展平衡， 行为相关脑区的神经回路。

Project Abstract We propose to investigate circuit homeostasis in the developing amygdala in a mouse model of Fragile X Syndrome (FXS) - a pervasive neurodevelopmental disorder (NDD) and a leading monogenic cause of autism. Many NDDs, such as FXS, are characterized by age-dependent symptom onset and regression in early life. Recent evidence, including our own publications, from monogenetic mouse models of NDDs reveal that critical periods of synaptic plasticity are altered in terms of onset, duration and offset. This altered critical period in NDDs is often referred to as a ‘sensitive time window’ – a time regulated window of synaptic impairment. Therefore, the identification of sensitive time windows has implications for understanding brain development and may indicate vulnerable periods for when therapeutic rescue is most effective. We have identified a brief period of enhanced synaptic plasticity in the developing amygdala in the Fmr1 knock out (KO) mouse model of FXS (Vislay et al., JNeurosci 2013). This is akin to a sensitive time window of plasticity in FXS. This discovery was built on our previous observation that inhibitory function is significantly depleted in Fmr1 KOs from postnatal day (P)21) through adult ages. We asked the question, “Are inhibitory circuits defective from birth or do they develop into defective circuits?”. Therefore, we examined the development of inhibitory circuit function during the first three weeks of postnatal development. At P10, when GABAA receptor mediated currents are inhibitory, Fmr1 KOs show decreased inhibitory function. However, surprisingly we observe that there is a homeostatic correction of defective inhibition between P14-16. This increase in inhibitory function is merely transient as this correction ultimately fails to be maintained by the P21 timepoint. By P21, synaptic inhibition falls below that of normal function through adulthood (Olmos-Serrano et al., JNeurosci 2010, Martin et al., JNeurophysiol 2014). We propose this increase in inhibitory function may be a “biomarker” for plasticity and thereby represents a sensitive time window in the developing fragile-x amygdala. In the present proposal, we will identify how this homeostatic fluctuation of inhibition occurs in Fmr1 KOs at key timepoints. The collective goal of these experiments is to determine how fluctuations in inhibitory function affect circuit function, structure, plasticity and behavior. In Specific Aim 1 we will explore this phenomenon with a comprehensive plan of experiments that will first examine how inhibitory circuits are altered in terms of function, connectivity and anatomy. In Specific Aim 2 we will determine how this period of homeostasis affects circuit plasticity and specific behaviors in early postnatal development. In summary, our proposed experiments will provide a clear identification of circuitry changes that alter the synaptic balance of developing circuits in a behaviorally relevant brain region for NDDs.