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Suppression of PIK3CA-driven epileptiform activity by acute pathway control
bioRxiv - Neuroscience Pub Date : 2021-05-16 , DOI: 10.1101/2021.03.03.433821
Achira Roy , Victor Z. Han , Angela M. Bard , Devin T. Wehle , Stephen E. P. Smith , Jan-Marino Ramirez , Franck Kalume , Kathleen J. Millen

Patients harboring mutations in the PI3K-AKT-MTOR signaling pathway often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion of them remain unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing patient-related activating mutation in PIK3CA are epileptic and acutely treatable with PI3K inhibition, irrespective of dysmorphology (Roy et al. 2015). Using the same mutant model, we have now identified physiological mechanisms underlying the dysregulated neuronal excitability and its acute attenuation. We show that Pik3ca-driven hyperexcitability in hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. These are distinct from mechanisms driving epilepsy in TSC/RHEB models. Further, we report that acute inhibition of PI3K or AKT, but not MTOR, suppresses the intrinsic epileptiform nature of the mutant neurons. These data represent an important step towards precision therapeutics against intractable epilepsy, using pathway drugs originally developed as anti-cancer agents.

中文翻译:

急性途径控制抑制PIK3CA驱动的癫痫样活动

在PI3K-AKT-MTOR信号传导途径中带有突变的患者通常会发生一系列神经发育障碍,包括癫痫病。他们中很大一部分仍然对常规抗癫痫药无反应。因此,了解突变特异性病理生理学对于分子靶向疗法至关重要。我们先前确定,在PIK3CA中表达患者相关激活突变的小鼠模型具有癫痫性,并且可以通过PI3K抑制进行急性治疗,无论其形态学如何(Roy等人,2015年)。使用相同的突变模型,我们现在已经确定了神经元兴奋性及其急性衰减失调的生理机制。我们显示在海马锥体神经元中Pik3ca驱动的过度兴奋是由多种非突触,细胞内在特性的变化介导的。这些与在TSC / RHEB模型中导致癫痫的机制不同。此外,我们报告说,对PI3K或AKT(而非MTOR)的急性抑制作用可抑制突变神经元的内在癫痫样性质。这些数据代表了使用最初开发为抗癌药的途径药物,针对难治性癫痫的精确治疗迈出的重要一步。
更新日期:2021-05-17
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