Neuroscience Institute, National Research Council (CNR), 56124 Pisa, Italy.
NEUROFARBA, University of Florence, 50134 Florence, Italy.
J Neurosci. 2020 Mar 25;40(13):2776-2788. doi: 10.1523/JNEUROSCI.0462-19.2020. Epub 2020 Feb 25.
Oligophrenin-1 (Ophn1) encodes a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID) in humans. Loss of function of Ophn1 leads to impairments in the maturation and function of excitatory and inhibitory synapses, causing deficits in synaptic structure, function and plasticity. Epilepsy is a frequent comorbidity in patients with Ophn1-dependent XLID, but the cellular bases of hyperexcitability are poorly understood. Here we report that male mice knock-out (KO) for Ophn1 display hippocampal epileptiform alterations, which are associated with changes in parvalbumin-, somatostatin- and neuropeptide Y-positive interneurons. Because loss of function of Ophn1 is related to enhanced activity of Rho-associated protein kinase (ROCK) and protein kinase A (PKA), we attempted to rescue Ophn1-dependent pathological phenotypes by treatment with the ROCK/PKA inhibitor fasudil. While acute administration of fasudil had no impact on seizure activity, seven weeks of treatment in adulthood were able to correct electrographic, neuroanatomical and synaptic alterations of Ophn1 deficient mice. These data demonstrate that hyperexcitability and the associated changes in GABAergic markers can be rescued at the adult stage in Ophn1-dependent XLID through ROCK/PKA inhibition. In this study we demonstrate enhanced seizure propensity and impairments in hippocampal GABAergic circuitry in Ophn1 mouse model of X-linked intellectual disability (XLID). Importantly, the enhanced susceptibility to seizures, accompanied by an alteration of GABAergic markers were rescued by Rho-associated protein kinase (ROCK)/protein kinase A (PKA) inhibitor fasudil, a drug already tested on humans. Because seizures can significantly impact the quality of life of XLID patients, the present data suggest a potential therapeutic pathway to correct alterations in GABAergic networks and dampen pathological hyperexcitability in adults with XLID.
寡啡磷蛋白 1（Ophn1）编码一种 Rho GTP 酶激活蛋白，其突变导致人类 X 连锁智力障碍（XLID）。Ophn1 的功能丧失导致兴奋性和抑制性突触的成熟和功能受损，导致突触结构、功能和可塑性缺陷。癫痫是 Ophn1 依赖性 XLID 患者的常见合并症，但过度兴奋的细胞基础知之甚少。本文报道，雄性 Ophn1 敲除（KO）小鼠表现出海马癫痫样改变，与 Parvalbumin、Somatostatin 和神经肽 Y 阳性中间神经元的变化相关。由于 Ophn1 的功能丧失与 Rho 相关蛋白激酶（ROCK）和蛋白激酶 A（PKA）活性增强有关，我们试图通过 ROCK/PKA 抑制剂 fasudil 来挽救 Ophn1 依赖性病理表型。虽然 fasudil 的急性给药对癫痫发作活动没有影响，但成年期 7 周的治疗能够纠正 Ophn1 缺陷小鼠的电生理、神经解剖和突触改变。这些数据表明，通过 ROCK/PKA 抑制，在 Ophn1 依赖性 XLID 的成年阶段，可以挽救过度兴奋和 GABA 能标志物相关的变化。本研究在 Ophn1 小鼠模型中证明了 X 连锁智力障碍（XLID）的癫痫易感性增强和海马 GABA 能回路受损。重要的是，通过 Rho 相关蛋白激酶（ROCK）/蛋白激酶 A（PKA）抑制剂 fasudil 挽救了增强的癫痫易感性和 GABA 能标志物的改变，这种药物已经在人类中进行了测试。因为癫痫发作会显著影响 XLID 患者的生活质量，因此本研究数据提示了一种潜在的治疗途径，可纠正 GABA 能网络的改变，并抑制 XLID 成人的病理性过度兴奋。
