Convergent Synaptic Mechanisms in Neurodevelopmental Disorders

不同的基因突变导致不同的神经发育障碍，但许多综合征 有相似的智力障碍。这个多学科项目的总体目标是， 在三位主要调查人员的特定专业知识的支持下，发现基本的 不同基因小鼠模型认知障碍的机制 神经发育障碍。我们假设上游的各种基因异常 汇聚在共同的下游机制上，在各个领域产生学习障碍 综合症。突触激活小GTP酶驱动树突棘肌动蛋白重塑 细胞骨架，一种远下游的机制，是持久突触可塑性的基础， 学习和记忆。我们将检验这一假设，即未能正确重组 突触下细胞骨架是神经发育障碍的共同终点，采用 建立脆性X(Fmr1)、Rett(MeCP2)、Down(Ts65Dn)和Angelman小鼠模型 (UBE3A)综合征。目标1将使用Theta Burst刺激和三种学习范式来测试 假设四个突变系都表现出突触GTP酶激活缺陷和 皮质和海马区肌动蛋白重塑。我们进一步建议将这些正常化 信号功能障碍将恢复认知功能。我们的初步数据显示 改变传入活动的间隔可以挽救海马长时程增强(LTP)，并且 改变认知训练的间隔可以挽救一种学习形式。目标2将测试 新发现的LTP计时规则将参与受损的肌动蛋白调控的假设 在突变体中级联并促进突触增强，以及类似的间隔训练 三种不同认知任务中的养生法将恢复突触GTP酶的激活和学习。 我们发现Fmr1和Ube3a小鼠在肌动蛋白调节、LTP和学习方面的损害 都是通过增加BDNF的可用性来拯救的，它促进了恢复肌动蛋白的信号传递 稳定状态。AIM 3将使用这些相同的下游端点进行临床前评估 药物学上的拯救。两种降低GTP酶激活门槛的化合物 野生型将在以下方面进行有效性测试：(1)逆转导致肌动蛋白的信号缺陷 稳定，(2)恢复LTP，(3)改善四种模型的认知成绩。 新的、广谱的行为和药物干预研究 加强下游机制的激活，并易于实施 临床上，将用统一的翻译解决一个基本的神经生物学假说 对改善多发性神经发育障碍患者认知能力的启示。

Diverse genetic mutations cause different neurodevelopmental disorders, yet many syndromes share similar intellectual impairments. The overarching aim of this multidisciplinary project, enabled by specific expertise from three principal investigators, is to discover fundamental mechanisms responsible for cognitive impairments across genetic mouse models of diverse neurodevelopmental disorders. We hypothesize that various upstream genetic abnormalities converge on common downstream mechanisms to produce learning disabilities across syndromes. Synaptic activation of small GTPases drives remodeling of the dendritic spine actin cytoskeleton, a far-downstream mechanism which underlies enduring synaptic plasticity, learning and memory. We will test the hypothesis that failure to properly reorganize the subsynaptic cytoskeleton is a shared endpoint across neurodevelopmental disorders, employing established mouse models of Fragile X (Fmr1), Rett (Mecp2), Down (Ts65Dn) and Angelman (Ube3a) syndromes. Aim 1 will use theta burst stimulation and three learning paradigms to test the hypothesis that the four mutant lines all exhibit deficits in synaptic GTPase activation and actin remodeling in cortex and hippocampus. We further propose that normalizing these signaling dysfunctions will restore cognitive functions. Our preliminary data indicate that changing the spacing of afferent activity rescues hippocampal long-term potentiation (LTP), and changing the spacing of cognitive training rescues one form of learning. Aim 2 will test the hypotheses that newly identified timing rules for LTP will engage the impaired actin regulatory cascades and facilitate synaptic potentiation in the mutants, and that analogous spaced training regimens in three different cognitive tasks will restore synaptic GTPase activation and learning. We discovered that impairments in actin regulation, LTP and learning in Fmr1 and Ube3a mice are rescued by increasing the availability of BDNF, which facilitates signaling to restore actin stabilization. Aim 3 will employ these same downstream endpoints for preclinical evaluation of pharmacological rescues. Two compounds that lower the threshold for GTPase activation in the wildtypes will be tested for efficacy in (1) reversing defects in signaling leading to actin stabilization, (2) restoring LTP, and (3) improving cognitive performance in the four models. Investigations of novel, broad spectrum behavioral and pharmacological interventions which enhance the activation of downstream mechanisms, and which can be readily implemented clinically, will address a fundamental neurobiological hypothesis with unifying translational implications for improving cognitive abilities in multiple neurodevelopmental disorders.