Excitatory and inhibitory synaptogenesis by FGFs and their role in epilepsy

描述（由申请人提供）：突触的精确组装对于大脑的正常功能至关重要。异常的突触形成或突触丢失导致许多神经系统疾病的进展。本文提出的研究目标是了解大脑突触形成的分子机制，然后利用这些信息开发治疗突触功能障碍引起的疾病的新疗法。突触是由突触前和突触后细胞之间的信号传导形成的。突触后细胞衍生的“突触前组织者”促进突触前轴突在突触接触部位局部分化为功能性神经末梢。我们进行了一个公正的搜索这样的突触前组织者，并确定成纤维细胞生长因子22（FGF 22），及其近亲FGF 7和FGF 10的分子，促进突触前神经末梢的分化。在大脑中，两种主要类型的突触，兴奋性和抑制性，需要在适当的位置形成。兴奋性和抑制性突触之间的不平衡被认为是导致各种神经系统疾病的原因，包括自闭症、精神分裂症、抽动秽语综合征和癫痫。我们最近发现，FGF 22和FGF 7分别促进兴奋性和抑制性突触前末梢的组织，作为海马中的靶源性突触前组织者。兴奋性或抑制性神经末梢的分化在缺乏FGF 22或FGF 7的突变体中特别受损。正如兴奋性/抑制性平衡的改变所预期的，FGF 22敲除（KO）小鼠具有抗性，而FGF 7 KO小鼠易于癫痫发作。这些结果表明，了解FGF介导的兴奋性和抑制性突触形成的确切机制将导致癫痫的新的治疗策略。在这里，我们解决（1）的机制差异的影响，由FGF 22和FGF 7兴奋性和抑制性突触前分化，（2）信号传导机制，介导的FGF的影响，（3）生理后果的FGF缺乏在体内，和（4）的作用，FGF在癫痫发生。对于这些研究，我们提出以下目标。目的1：确定FGF 22和FGF 7在体内的定位及其在不同突触后部位的动态分布。目的2：检测FGF 22和FGF 7是否通过不同的FGF受体和信号通路进行信号传导，以获得其不同的突触前效应。目的3：描述脑发育过程中FGF失活的功能后果。目的4：确定FGF是否参与癫痫回路形成过程中的发展或脑损伤后。我们将使用分子遗传学、细胞生物学、生物化学、电生理学和成像技术的综合组合来实现这些目标。预计这项研究将揭示特定突触形成的新机制，并提出治疗突触形成不当导致的脑疾病（如癫痫）的新策略。

DESCRIPTION (provided by applicant): Precise assembly of synapses is critical for proper functioning of the brain. Abnormal synapse formation or synaptic loss contributes to the progression of many neurological disorders. The goals of the research proposed here are to understand the molecular mechanisms underlying synapse formation in the brain and then use this information to develop new treatments for diseases resulting from synaptic malfunction. Synapses are formed by signaling between presynaptic and postsynaptic cells. Postsynaptic cell-derived "presynaptic organizers" promote local differentiation of presynaptic axons into functional nerve terminals at sites of synaptic contact. We performed an unbiased search for such presynaptic organizers and identified fibroblast growth factor 22 (FGF22), and its close relatives FGF7 and FGF10 as molecules that promote differentiation of presynaptic nerve terminals. In the brain, two major types of synapses, excitatory and inhibitory, need to be formed at their appropriate sites. An imbalance between excitatory and inhibitory synapses has been proposed to contribute to various neurological disorders including autism, schizophrenia, Tourette syndrome and epilepsy. We have recently found that FGF22 and FGF7 promote the organization of excitatory and inhibitory presynaptic terminals, respectively, as target-derived presynaptic organizers in the hippocampus. The differentiation of excitatory or inhibitory nerve terminals is specifically impaired in mutants lacking FGF22 or FGF7. As expected from the alterations in excitatory/inhibitory balance, FGF22 knockout (KO) mice are resistant and FGF7KO mice are prone to epileptic seizures. These results indicate that understanding the precise mechanisms of FGF-mediated excitatory and inhibitory synapse formation will lead to novel treatment strategies for epilepsy. Here we address (1) the mechanisms underlying the differential effects by FGF22 and FGF7 on excitatory and inhibitory presynaptic differentiation, (2) the signaling mechanisms that mediate the effects of FGFs, (3) physiological consequences of FGF deficiency in vivo, and (4) the role of FGFs in epileptogenesis. For these studies, we propose the following aims. Aim 1: Determine the in vivo localization of FGF22 and FGF7 and their dynamic distribution to distinct postsynaptic sites. Aim 2: Examine whether FGF22 and FGF7 signal through different FGF receptors and signaling pathways for their differential presynaptic effects. Aim 3: Delineate the functional consequences of FGF inactivation during brain development. Aim 4: Determine whether FGFs are involved in epileptic circuit formation during development or after brain insults. We will use an integrated combination of molecular genetic, cellular biological, biochemical, electrophysiological and imaging techniques to address these aims. It is anticipated that this study will reveal novel mechanisms underlying specific synapse formation and suggest novel strategies for treating brain disorders, such as epilepsy, that result from improper synapse formation.