Defining Plasticity and Homeostasis in Fragile X Syndrome

项目摘要 我们建议在脆性X小鼠模型中研究发育中的杏仁核的电路稳态。 综合征(FXS)-一种弥漫性神经发育障碍(NDD)，是导致 自闭症。许多NDD，如FXS，其特征是年龄相关性症状的出现和消退 早年的生活。最近的证据，包括我们自己的出版物，来自单基因小鼠模型的NDDS揭示 突触可塑性的关键时期根据起始、持续时间和偏移量而改变。这改变了危急关头 NDDS中的周期通常被称为‘敏感时间窗’--突触的时间调节窗 减损。因此，敏感时间窗的识别对于理解大脑具有重要意义 并可能指示治疗抢救最有效的脆弱时期。 我们发现Fmr1区发育中的杏仁核有一个短暂的突触可塑性增强时期。 FXS的敲除(KO)小鼠模型(Vislay等人，JNeurosci 2013)。这类似于一个敏感的时间窗口 FXS的可塑性。这一发现是建立在我们之前观察到的抑制功能显著 从出生后(P)21天到成年，Fmr1 KO消耗殆尽。我们问了这个问题，“是抑制性的 电路从出生就有缺陷，还是会发展成有缺陷的电路？因此，我们研究了 在出生后的头三周内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，Fmr1KO表现为抑制功能减弱。然而， 令人惊讶的是，我们观察到在P14-16之间存在缺陷抑制的动态平衡校正。这 抑制功能的增加只是暂时的，因为这种校正最终无法由P21维持 时间点。到P21，突触抑制下降到成年期的正常功能以下(Olmos-Serrano 等人，JNeurosci 2010，Martin等人，JNeuroPhysiol 2014)。我们提出这种抑制功能的增加可能 作为可塑性的“生物标记物”，因此代表着发展中的脆性-x的一个敏感的时间窗口 杏仁核。 在目前的提案中，我们将确定这种抑制的动态平衡波动是如何在Fmr1 KO中发生的 关键时间点。这些实验的共同目标是确定抑制性波动如何发挥作用 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 有一个全面的实验计划，首先将检查抑制电路是如何改变的 功能、连通性和解剖学。在具体目标2中，我们将确定这段动态期是如何 影响电路可塑性和出生后早期发育的特定行为。总而言之，我们的建议 实验将为改变发育中突触平衡的回路变化提供明确的识别 在与行为相关的大脑区域中产生NDDS的回路。

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.