BACKGROUND Loss-of-function SYNGAP1 mutations cause a neurodevelopmental disorder characterized by intellectual disability and epilepsy. SYNGAP1 is a Ras GTPase-activating protein that underlies the formation and experience-dependent regulation of postsynaptic densities. The mechanisms that contribute to this proposed monogenic cause of intellectual disability and epilepsy remain unresolved. METHODS We established the phenotype of the epileptogenesis in a Syngap1+/- mouse model using 24-hour video electroencephalography (vEEG)/electromyography recordings at advancing ages. We administered an acute low dose of perampanel, a Food and Drug Administration-approved AMPA receptor (AMPAR) antagonist, during a follow-on 24-hour vEEG to investigate the role of AMPARs in Syngap1 haploinsufficiency. Immunohistochemistry was performed to determine the region- and location-specific differences in the expression of the GluA2 AMPAR subunit. RESULTS A progressive worsening of the epilepsy with emergence of multiple seizure phenotypes, interictal spike frequency, sleep dysfunction, and hyperactivity was identified in Syngap1+/- mice. Interictal spikes emerged predominantly during non-rapid eye movement sleep in 24-hour vEEG of Syngap1+/- mice. Myoclonic seizures occurred at behavioral-state transitions both in Syngap1+/- mice and during an overnight EEG from a child with SYNGAP1 haploinsufficiency. In Syngap1+/- mice, EEG spectral power analyses identified a significant loss of gamma power modulation during behavioral-state transitions. A significant region-specific increase of GluA2 AMPAR subunit expression in the somas of parvalbumin-positive interneurons was identified. CONCLUSIONS Acute dosing with perampanel significantly rescued behavioral state-dependent cortical gamma homeostasis, identifying a novel mechanism implicating Ca2+-impermeable AMPARs on parvalbumin-positive interneurons underlying circuit dysfunction in SYNGAP1 haploinsufficiency.

中文翻译：

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低剂量吡仑帕奈可挽救癫痫 Syngap1+/- 小鼠中与小清蛋白中间神经元 GluA2 上调相关的皮质伽马失调

背景 功能丧失性 SYNGAP1 突变会导致以智力障碍和癫痫为特征的神经发育障碍。SYNGAP1 是一种 Ras GTP 酶激活蛋白，是突触后密度形成和依赖经验调节的基础。促成这一拟议的智力障碍和癫痫单基因原因的机制仍未得到解决。方法 我们使用 24 小时视频脑电图 (vEEG)/肌电图记录建立了 Syngap1+/- 小鼠模型中癫痫发生的表型。我们在后续 24 小时 vEEG 期间给予急性低剂量吡仑帕奈，一种食品和药物管理局批准的 AMPA 受体 (AMPAR) 拮抗剂，以研究 AMPAR 在 Syngap1 单倍剂量不足中的作用。进行免疫组织化学以确定 GluA2 AMPAR 亚基表达的区域和位置特异性差异。结果 在 Syngap1+/- 小鼠中发现癫痫进行性恶化，出现多种癫痫发作表型、发作间期尖峰频率、睡眠功能障碍和多动症。在 Syngap1+/- 小鼠的 24 小时 vEEG 中，发作间期尖峰主要出现在非快速眼动睡眠期间。肌阵挛发作发生在 Syngap1+/- 小鼠的行为状态转换期间，以及 SYNGAP1 单倍剂量不足儿童的夜间脑电图中。在 Syngap1+/- 小鼠中，EEG 频谱功率分析确定了行为状态转换期间伽马功率调制的显着损失。确定了小清蛋白阳性中间神经元胞体中 GluA2 AMPAR 亚基表达的显着区域特异性增加。结论 吡仑帕奈的急性给药显着挽救了行为状态依赖性皮层伽马稳态，确定了一种新机制，该机制涉及 SYNGAP1 单倍剂量不足的小清蛋白阳性中间神经元上 Ca2+ 不可渗透的 AMPAR。