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 有着相似的智力缺陷这一多学科项目的总体目标是， 通过三位主要研究者的专业知识， 不同遗传小鼠模型中认知障碍的机制 神经发育障碍我们假设各种上游基因异常 汇聚在共同的下游机制，以产生跨 综合征小GTP酶的突触激活驱动树突棘肌动蛋白的重塑 细胞骨架，一种作为持久突触可塑性基础的远下游机制， 学习和记忆。我们将检验一个假设，即如果不能正确地重组 突触下细胞骨架是神经发育障碍的共同终点， 建立了脆性X染色体（Fragile X，Fmr 1）、Rett（Mecp 2）、Down（Ts65Dn）和Angelman小鼠模型 （Ube3a）综合征。目标1将使用θ爆发刺激和三种学习范式来测试 假设四个突变株系都表现出突触GT3激活缺陷， 皮质和海马肌动蛋白重塑。我们进一步建议， 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挽救海马长时程增强（LTP）， 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 假设新发现的LTP的时间规则将参与受损的肌动蛋白调节， 级联并促进突变体的突触增强，类似的间隔训练 在三种不同的认知任务中的治疗方案将恢复突触GT3激活和学习。 我们发现，在Fmr1和Ube3a小鼠中，肌动蛋白调节、LTP和学习障碍 通过增加脑源性神经营养因子的可用性来拯救，这有助于恢复肌动蛋白的信号传导。 稳定化目标3将采用这些相同的下游终点进行临床前评价， 药物救援两种化合物，降低阈值的GT3激活在 将测试野生型在以下方面的功效：（1）逆转导致肌动蛋白 稳定，（2）恢复LTP，（3）改善四种模型中的认知表现。 研究新的、广谱的行为和药理学干预， 增强下游机制的激活，并且易于实施 临床上，将解决一个基本的神经生物学假设与统一的翻译 对改善多种神经发育障碍的认知能力的意义。

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.