BDNF and the Restoration of Synaptic Plasticity in Fragile X and Autism

在人类认知障碍的动物模型中，存在活动诱导的树突棘肌动蛋白细胞骨架重塑和依赖于此的长时程增强(LTP)过程的紊乱。我们的项目已经证明，脑源性神经营养因子(BDNF)可以在几个模型中拯救这两个过程。这表明，脊柱肌动蛋白重塑是受各种认知功能障碍影响的最终共同途径，通过对这一过程的影响，BDNF可以抵消认知障碍。项目1将对脆性X综合征(FXS)(一种智力低下综合征)的Fmr1-KO小鼠模型进行测试 自闭症的易感性)。Fmr1-Kos具有异常的LTP阈值和稳定性。我们还发现，它们也缺乏正常活性诱导的Rac GTP酶和p21激活的激酶(PAK)信号，该信号被认为是介导F-肌动蛋白和LTP稳定的，但BDNF的注入仍然可以稳定突变体中的增强。拟议的研究将使用急性海马片和活体准备来了解F-肌动蛋白调节的缺陷，并测试Ampakine-BDNF策略恢复Fmr1-KOS的功能。AIM 1将测试失败的RAC激活是否解释了KO中的信号和LTP损伤，以及这是否次要于突触整合素功能的变化。AIM 2将测试BDNF输注是否通过PAK恢复脊柱信号，或驱动其他系统影响KO中脊柱F-肌动蛋白和LTP的稳定。然后，AIM 3将测试体内治疗(Ampakine或Ampakine+MPEP)是否能类似地恢复体外评估的肌动蛋白调节和LTP。Aim 4将使用一种非监督学习范式来测试上调BDNF是否导致通过BDNF的TrkB受体的信号增强以及 突变体中的探索性行为和学习；这些研究还将测试突触激活的拓扑结构在突变体中是否异常，并与BDNF信号的增加相关地正常化。最后，Aim 5将测试TBS诱导的LTP以及在Fmr1-KO小鼠中受到干扰的肌动蛋白信号转导步骤是否在其他自闭症表型动物模型中受到干扰并被BDNF纠正：这项工作将评估在BTBR T[+]Tf/J小鼠和结节性硬化症复杂模型小鼠中的效果。把这些放在一起 研究将确定FXS模型小鼠LTP稳定性缺陷的潜在机制，确定同样的过程是否在其他具有自闭症特征的小鼠品系中受到干扰，并测试增加内源性BDNF是否是纠正自闭症相关认知疾病模型中学习和记忆细胞机制障碍的有效治疗策略。

In animal models of human cognitive impairment there are disturbances in activity-induced remodeling of the dendritic spine actin cytoskeleton and processes of long term potentiation (LTP) that depend upon it. Our program has shown that Brain-derived neurotrophic factor (BDNF) can rescue both processes in several models. This suggests that spine actin remodeling is a final common path impacted in various conditions of cognitive dysfunction and that, through effects on this process, BDNF can offset cognitive deficits. Project 1 will test this for the Fmr1-KO mouse model of Fragile-X Syndrome (FXS) (a mental retardation syndrome with susceptibility for autism). The Fmr1-KOs have abnormal LTP threshold and stabilization. We find they also lack of normal activity-induced Rac GTPase > p21 activated kinase (PAK) signaling proposed to mediate F-actin and LTP stabilization, but BDNF infusion can still stabilize potentiation in the mutants. Proposed studies will use acute hippocampal slices and in vivo preparations to understand deficiencies in F-actin regulation, and to test an ampakine-BDNF strategy for restoration of function in Fmr1-KOs. Aim 1 will test if failed Rac activation accounts for signaling and LTP impairments in the KOs and if this is secondary to changes in synaptic integrin function. Aim 2 will test if BDNF infusion restores spine signaling through PAK or drives other systems to effect stabilization of spine F-actin and LTP in the KOs. Aim 3 will then test if in vivo treatments (ampakine or ampakine+MPEP) that increase BDNF protein content similarly restore actin regulation and LTP as assessed ex-vivo. Aim 4 will use an unsupervised learning paradigm to test if upregulating BDNF leads to heightened signaling through BDNF's TrkB receptor and a normalization of exploratory behavior and learning in the mutants; these studies will also test if the topography of synapse activation is abnormal in the mutants and normalized in association with increases in BDNF signaling. Finally, Aim 5 will test if TBS-induced LTP, and steps in actin signaling that are perturbed in the Fmr1-KO mice, are disturbed in other animal models of autistic phenotype and corrected by BDNF: this work will evaluate effects in the BTBR T[+] tf/J mice and Tuberous Sclerosis complex model mice. Together these studies will identify mechanisms underlying deficits in LTP stabilization in FXS model mice, determine if the same processes are disturbed in other mouse strains with features of autism, and test if increasing endogenous BDNF is an effective therapeutic strategy for correcting impairments in the cellular mechanisms of learning and memory in models of cognitive conditions associated with autism.