Exploring the role of oxytocin in the regulation of neuronal excitability

项目总结 电压门控钠通道(VGSCs)功能障碍是几种形式的灾难性疾病的原因 儿童脑病。已发现1000多个VGSC SCN1A功能缺失突变 是Drave氏综合征(DS)的主要原因，其特征是早期反复发作- 生活热性癫痫(FSS)、严重的无热性癫痫、认知和行为障碍，以及15%-20%的死亡率 费率。VGSC SCN8A的突变最近是在2012年被发现的，并且已经有200多个功能获得 据报道，SCN8A突变存在于具有一系列临床特征的患者中，包括灾难性的 难治性儿童癫痫、自闭症、智力残疾和发育迟缓。不幸的是， 大多数抗癫痫药物(AEDs)未能充分治疗范围广泛的严重癫痫发作和行为 SCN1A型和SCN8A型癫痫患者的表型。因此，尽管最近在以下方面取得了进展 对于DS的药物治疗，仍然需要开发更有效、更持久的治疗方法 副作用更少。众所周知，神经肽在动物研究中显示出巨大的控制前景 癫痫发作和改善行为异常；然而，它们不容易跨越血脑屏障 并在全身给药时迅速代谢。因此，大脑外显性差是阻碍 这些治疗方法的临床应用前景看好。为了克服这一挑战，我们开发并验证了一个 狂犬病病毒糖蛋白偶联纳米粒包裹神经肽的研究进展 (RVG)。利用这种方法，我们发现纳米颗粒包裹的催产素(NP-1)鼻腔给药。 OT)极大地提高了大脑的外显率和OT的能力，从而使 SCN1A和SCN8A功能障碍小鼠模型对癫痫发作的抵抗。我们还扩展了我们的战略 包裹神经肽Y(NP-NPY)，并同样观察到其授予能力的强劲改善 癫痫抵抗。在拟议的研究中，我们将建立NP-OT和NP-NPY改善的能力 Scn1a和Scn8a突变小鼠的自发性癫痫发作和行为异常(目标1)。虽然这个角色 催产素在社会行为中的作用已得到很好的研究，但对其调节癫痫发作的机制知之甚少 敏感度。因此，我们还将确定对这种能力有贡献的细胞和神经回路机制 OT的作用是提高Scn1a和Scn8a突变体的抗惊厥能力(目标2)。我们的长远目标是发展 脑部注射神经肽治疗癫痫等疾病的安全有效途径 神经紊乱。

PROJECT SUMMARY Dysfunction of voltage-gated sodium channels (VGSCs) is responsible for several forms of catastrophic childhood encephalopathies. Over 1000 loss-of-function mutations in the VGSC SCN1A have been identified during the last two decades and are the main cause of Dravet syndrome (DS), characterized by recurrent early- life febrile seizures (FSs), severe afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. Mutations in the VGSC SCN8A were more recently identified in 2012, and already over 200 gain-of-function SCN8A mutations have been reported in patients with a range of clinical features including catastrophic treatment-resistant childhood epilepsy, autism, intellectual disability and developmental delay. Unfortunately, most anti-epileptic drugs (AEDs) fail to adequately treat the broad range of severe seizures and behavioral phenotypes in patients with SCN1A- and SCN8A-derived epilepsy. Thus, despite recent progress in pharmacological treatments for DS, there remains a need to develop more effective, longer lasting treatments with fewer side effects. Neuropeptides are well known in animal studies to show great promise for controlling seizures and ameliorating behavioral abnormalities; however, they do not readily cross the blood brain barrier and are rapidly metabolized when given systemically. Thus, poor brain penetrance is a critical barrier to the clinical application of these promising therapeutics. To overcome this challenge, we developed and validated an approach based on the encapsulation of neuropeptides in nanoparticles conjugated to rabies virus glycoprotein (RVG). Using this approach, we have found that intranasal delivery of nanoparticle-encapsulated oxytocin (NP- OT) greatly increases brain penetrance and the capacity of OT to confer robust and sustained increases in resistance to seizures in mouse models of SCN1A and SCN8A dysfunction. We have also extended our strategy to encapsulate neuropeptide Y (NP-NPY), and similarly observed a robust improvement in its ability to confer seizure resistance. In the proposed study, we will establish the ability of NP-OT and NP-NPY to ameliorate spontaneous seizures and behavioral abnormalities in Scn1a and Scn8a mouse mutants (Aim 1). While the role of OT in social behavior is well-studied, less is known about the mechanisms by which it modulates seizure susceptibility. Thus, we will also identify the cellular and neural circuit mechanisms that contribute to the ability of OT to increase seizure resistance in the Scn1a and Scn8a mutants (Aim 2). Our long-term goal is to develop safe and effective approaches for the brain delivery of neuropeptides for the treatment of epilepsy and other neurological disorders.